ArticleLiterature Review

IL-1 Superfamily Members and Periodontal Diseases

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)–1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an “alarmin” via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... We identified (Fig. 2f): (i) cluster 1 (pro-inflammatory: IL-1α, IL-1β, TNF-α, GMCSF; anti-inflammatory: IL-1RA) composed of cytokines expressed at low levels before the microbiome inoculum, and increased transiently at day1 (with the exception of IL-1α); (ii) cytokines in cluster 2 (pro-inflammatory: IL-8, IL-6-MCP1) were already released at day 0 and, after a reduction in their levels at day1, were subsequently not detected; (iii) cluster 3 (anti-inflammatory: INF-γ) and cluster 4 (antiinflammatory: IL-4, IL-10) were comprised of cytokines present at day 0 with evidence of greater release after the microbial challenge throughout 7 days. Pro-inflammatory cytokines IL-1α and β, secreted by epithelial and stromal cells upon microbiome stimulation, are pivotal in the recruitment of immune cells 41,45 and are subsequently modulated by anti-inflammatory cytokine IL-1RA during tissue homeostasis 45 . Accordingly, we found these cytokines clustered together (cluster1). ...
... We identified (Fig. 2f): (i) cluster 1 (pro-inflammatory: IL-1α, IL-1β, TNF-α, GMCSF; anti-inflammatory: IL-1RA) composed of cytokines expressed at low levels before the microbiome inoculum, and increased transiently at day1 (with the exception of IL-1α); (ii) cytokines in cluster 2 (pro-inflammatory: IL-8, IL-6-MCP1) were already released at day 0 and, after a reduction in their levels at day1, were subsequently not detected; (iii) cluster 3 (anti-inflammatory: INF-γ) and cluster 4 (antiinflammatory: IL-4, IL-10) were comprised of cytokines present at day 0 with evidence of greater release after the microbial challenge throughout 7 days. Pro-inflammatory cytokines IL-1α and β, secreted by epithelial and stromal cells upon microbiome stimulation, are pivotal in the recruitment of immune cells 41,45 and are subsequently modulated by anti-inflammatory cytokine IL-1RA during tissue homeostasis 45 . Accordingly, we found these cytokines clustered together (cluster1). ...
... In addition, it is important to notice that IL-1α/β was only transiently upregulated at day 1. Excessive and prolonged secretion of IL-1α/β causes collagen degradation and bone resorption in the periodontium 45 . In addition, IL-4, an anti-inflammatory cytokine, was detected throughout the culture period. ...
Article
Full-text available
The human body houses many distinct and interconnecting microbial populations with long-lasting systemic effects, where the oral cavity serves as a pathogens’ reservoir. The correlation of different disease states strongly supports the need to understand the interplay between the oral tissue niche and microbiome. Despite efforts, the recapitulation of gingival architecture and physiological characteristics of the periodontal niche has yet to be accomplished by traditional cultural strategies. Here, we are showing for the first time the investigation of host–microbiome interactions in healthy conditions within a human oral tissue model over seven days. Our results indicated long-term host and microbiome viability, host barrier integrity, phenotypic functional response, and preservation of healthy microbial populations and interbacterial dialogs. This in vitro platform can maintain tissue homeostasis at the interface of the periodontal niche, thus, offering opportunities to identify predictive disease biomarkers and to develop intervention strategies to promote oral and overall health.
... IL-1β is one of the major pro-inflammatory cytokines in relation to immune-inflammatory response and osteoclastic bone resorption in periodontitis [2,21]. It induces the release of other proinflammatory cytokines, chemokines and extracellular matrix-degrading enzymes, which leads to periodontal tissue destruction [21]. ...
... IL-1β is one of the major pro-inflammatory cytokines in relation to immune-inflammatory response and osteoclastic bone resorption in periodontitis [2,21]. It induces the release of other proinflammatory cytokines, chemokines and extracellular matrix-degrading enzymes, which leads to periodontal tissue destruction [21]. Elevated levels of IL-1β in GCF, saliva and serum have been associated with periodontitis [22][23][24][25], making it a potential biomarker for diagnosis and treatment monitoring [21]. ...
... It induces the release of other proinflammatory cytokines, chemokines and extracellular matrix-degrading enzymes, which leads to periodontal tissue destruction [21]. Elevated levels of IL-1β in GCF, saliva and serum have been associated with periodontitis [22][23][24][25], making it a potential biomarker for diagnosis and treatment monitoring [21]. ...
Article
Full-text available
Objectives Activin-A belongs to the transforming growth factor-beta superfamily and is a multifunctional cytokine that plays a role in inflammation, immune response, tissue repair and regeneration. Proinflammatory cytokine interleukin-1beta (IL-1β) can increase Activin-A expression in various cell types. This study aims to evaluate gingival crevicular fluid (GCF) and salivary Activin-A and IL-β levels in stage III periodontitis. Materials and methods 23 patients with stage III periodontitis, 26 with gingivitis and 26 periodontally healthy individuals were included. Full-mouth clinical periodontal indices were recorded, unstimulated whole saliva and GCF samples were obtained, Activin-A and IL-1β total amounts were determined by ELISA. Statistical comparisons were performed using non-parametric tests. Receiver operating characteristics curve was used for estimating the area under the curve (AUC). Results Periodontitis group exhibited significantly lower GCF Activin-A levels but higher IL-1β levels than the periodontally healthy group (p < 0.05). Gingivitis group had similar GCF Activin-A and IL-1β levels to the periodontitis and periodontally healthy groups (p > 0.05). Salivary Activin-A and IL-1β concentrations were similar among study groups (p > 0.05). GCF Activin-A level showed an excellent diagnostic performance (an AUC value of 0.82 with 87% sensitivity) to discriminate periodontitis from periodontal health. Conclusions For the first time, this study demonstrated oral biofluid levels of Activin-A in periodontal health and diseases. Within the limits of the study, it might be suggested that diseased sites in periodontitis are associated with reduced Activin-A and increased IL-1β levels in GCF. Clinical relevance. Reduced GCF Activin-A levels and the accompanying increase in IL-1β might be associated with diseased sites in stage III periodontitis.
... Recent investigations have begun to emphasize that this chronic inflammation with tissue destruction is not a unidirectional process. Molecular studies have identified antiinflammatory cytokines (53-59), pathways of inflammation resolving molecules (60)(61)(62)(63)(64), and molecules recognized as dangerassociated molecular patterns (DAMPs) or alarmins (65)(66)(67)(68) recognized by host cells to help minimize tissue damage and help to control destructive processes. ...
... These DAMPs or alarmins comprise a wide array of cell surface and intracellular components that reflect disruption of the integrity of cells. The host has developed a variety of detectors for these molecules and evolved to respond to reestablish homeostasis and stimulate resolution and healing (67,96,98,100,109,(110)(111)(112). Also clear is that these biomolecules are elevated in chronic inflammatory diseases, including periodontitis (##). ...
... Fold changes compared to baseline (healthy) tissues for each age group. Frontiers in Oral Health of cytokines, is a nuclear protein that is released from damaged cells as an alarmin (67). The cytokine was also elevated in GCF and plasma in generalized aggressive periodontitis patients compared to periodontally healthy or chronic periodontitis (116). ...
Article
Full-text available
Introduction Periodontitis is delineated by a dysbiotic microbiome at sites of lesions accompanied by a dysregulated persistent inflammatory response that undermines the integrity of the periodontium. The interplay of the altered microbial ecology and warning signals from host cells would be a critical feature for maintaining or re-establishing homeostasis in these tissues. Methods This study used a nonhuman primate model ( Macaca mulatta ) with naturally-occurring periodontitis ( n = 34) and experimental ligature-induced periodontitis ( n = 36) to describe the features of gene expression for an array of damage-associate molecular patterns (DAMPs) or alarmins within the gingival tissues. The animals were age stratified into: ≤3 years (Young), 7–12 years (Adolescent), 12–15 years (Adult) and 17–23 years (Aged). Gingival tissue biopsies were examined via microarray. The analysis focused on 51 genes representative of the DAMPs/alarmins family of host cell warning factors and 18 genes associated with tissue destructive processed in the gingival tissues. Bacterial plaque samples were collected by curette sampling and 16S rRNA gene sequences used to describe the oral microbiome. Results A subset of DAMPs/alarmins were expressed in healthy and naturally-occurring periodontitis tissues in the animals and suggested local effects on gingival tissues leading to altered levels of DAMPs/alarmins related to age and disease. Significant differences from adult healthy levels were most frequently observed in the young and adolescent animals with few representatives in this gene array altered in the healthy aged gingival tissues. Of the 51 target genes, only approximately ⅓ were altered by ≥1.5-fold in any of the age groups of animals during disease, with those increases observed during disease initiation. Distinctive positive and negative correlations were noted with the DAMP/alarmin gene levels and comparative expression changes of tissue destructive molecules during disease across the age groups. Finally, specific correlations of DAMP/alarmin genes and relative abundance of particular microbes were observed in health and resolution samples in younger animals, while increased correlations during disease in the older groups were noted. Conclusions Thus, using this human-like preclinical model of induced periodontitis, we demonstrated the dynamics of the activation of the DAMP/alarmin warning system in the gingival tissues that showed some specific differences based on age.
... Similarly, the IL-1 receptor antagonist gene, IL1RN, encodes IL-Ra that inhibits IL-1B activity by competitive binding to IL-1 receptors [19][20][21][22], which acts as an anti-inflammatory cytokine and may even favour osteogenic differentiation of gingival-derived mesenchymal stem cells (GMSC) [21], also shows statistically significant down-regulated expression (p = 0.048) in the group of PD+IR+ patients. This result is especially interesting, since IL-1Ra has been described to protect GMSC cell viability and osteogenic capacity through the irruption of the NF-κB signaling pathway mediated by TLR-4 and activated by P. gingivalis-LPS [21]. ...
... This result is especially interesting, since IL-1Ra has been described to protect GMSC cell viability and osteogenic capacity through the irruption of the NF-κB signaling pathway mediated by TLR-4 and activated by P. gingivalis-LPS [21]. Therefore, IL-1Ra is considered a strong defence against periodontitis, whose deficiency influences the most serious destruction of periodontal tissue in a murine experimental model of periodontitis [20]. Previous studies showed that mice without IL-1Ra have greater colonization of Aggregatibacter Actinomycetemcomitans, one of the bacteria most associated with incisor-molar [22] pattern periodontitis, formerly known as aggressive periodontitis, and from which patients with Down syndrome often suffer. ...
... Despite the fact that our study group shows the down-regulated IL1B gene, since, according to studies, inadequate or even increased IL-1Ra secretion seems not to be enough to counteract the deleterious effects of IL-1B [20], we could speculate that the other way around, the lower expression of IL-1B is not important enough to not observe the deleterious effects of this proinflammatory cytokine in patients who also show reduced expression of IL-1Ra, dependent on a regulation to loss of its IL1RN encoded gene. ...
Article
Full-text available
Down syndrome patients show success rates in dental implants much lower than those observed in the general population. This retrospective case-control study aimed to identify possible genes that are related to the regulation of inflammatory responses and bone metabolism related to periimplantitis and implant loss, as well as genes related to bone quality. This process involved using the functional analysis of the gene expression software Transcriptome Analysis Console (TAC version 4.0 Applied BiosystemsTM, Thermo Fisher Scientific, Waltham, MA, USA) and a search for possible candidate genes involved. The focus was placed on the 93 genes related to periodontitis, periimplantitis, bone loss, implant loss, and genes related to bone quality and regulators underlying the establishment and maintenance of osseointegration. Five genes showed statistically significant results (p < 0.05) in our comparison. Four of them, IL1B (p = 0.023), IL1RN (p = 0.048), BGLAP (p = 0.0372) and PTK2 (p = 0.0075) were down-regulated in the periodontal disease and implant rejection group, and only one was overexpressed: FOXO1A (p = 0.0552). The genes with statistically significant alterations described in this article determine that the group of Down syndrome patients with periodontal disease and implant failure is a group of patients genetically susceptible to suffering from both conditions together.
... The two main inflammatory cytokines measured across all three studies were TNF-α and IL-1β, both of which are inflammatory cytokines found in inflamed periodontal tissues and are principal inducers of effector molecules that cause bone remodeling (Papathanasiou et al., 2020). They are also important markers for periodontitis progression and severity (Gomes et al., 2016). ...
... They are also important markers for periodontitis progression and severity (Gomes et al., 2016). IL-1β increases bone resorption by increasing osteoclastogenesis and exacerbates vasodilation, inflammatory cell chemotaxis, and collagen degradation (Papathanasiou et al., 2020). This is achieved through the upregulation of matrix metalloproteinase secretion (Papathanasiou et al., 2020). ...
... IL-1β increases bone resorption by increasing osteoclastogenesis and exacerbates vasodilation, inflammatory cell chemotaxis, and collagen degradation (Papathanasiou et al., 2020). This is achieved through the upregulation of matrix metalloproteinase secretion (Papathanasiou et al., 2020). TNF-α is crucial to the initiation and perpetuation of inflammatory and tissue-destructive responses in periodontitis (Tervahartiala et al., 2001). ...
Article
Full-text available
Objective: This review was conducted to assess the effectiveness of xylitol against Porphyromonas gingivalis anaerobic species, a key microbe contributing to periodontal disease pathogenesis. Material and methods: Relevant studies published on seven online databases (Cochrane, Ovid, Pubmed, Pubmed Central, Scopus, Google Scholar, and Web of Science) were included in accordance with the PRISMA guidelines. Inclusion criteria allowed all study designs involving xylitol and P. gingivalis, literature published since the year 2000, and all xylitol delivery forms. Results: The initial search yielded 186 papers. After the removal of duplicates, five reviewers screened every article for eligibility and seven articles were selected for data extraction. Four out of seven included studies assessed the dose-dependent effect of xylitol on P. gingivalis growth, two studies assessed the effect of xylitol on P. gingivalis-induced cytokine expression, and one study assessed both domains. Conclusions: From the in vitro studies included in this systematic review, there is some evidence of xylitol's inhibitory effect on P. gingivalis. However, more evidence derived from in vivo studies is required to confirm its effectiveness warranting their routine use.
... ; https://doi.org/10.1101/2024.01.28.577629 doi: bioRxiv preprint (Figure 2f): 1) cluster 1 (pro-inflammatory: IL-1a, IL-1b, TNF-a, GMCSF; anti-inflammatory: IL-1RA) composed of cytokines expressed at low levels before the microbiome inoculum that increased transiently at day1 (with the exception of IL-1a); 2) cytokines in cluster 2 (pro-inflammatory: IL-8, IL-6-MCP1) were already released at day0 and, after a drop in their levels at day1, were subsequently not detected; 3) cluster3 (anti-inflammatory: INF-g) and cluster4 (anti-inflammatory: IL-4, IL-10) were composed of cytokines that were present at day 0 and increased their levels after the microbial challenge for all seven days. Of note are the pro-inflammatory cytokines IL-1a-b, secreted by epithelial and stromal cells after being stimulated by microbial population, which are pivotal in the recruitment of immune cells 57,61 and whose levels are stabilized in tissue homeostasis by anti-inflammatory cytokine IL-1Ra 61 . Accordingly, we found these cytokines clustered together (cluster1). ...
... Accordingly, we found these cytokines clustered together (cluster1). In addition, it is important to notice that IL-1a-b are only transiently upregulated at day1; in fact, excessive and prolonged secretion of IL-1a-b causes collagen degradation and bone resorption in the periodontium 61 . In addition, IL-4, an anti-inflammatory cytokine, was detected throughout the culture period. ...
Preprint
Host-oral microbiome interactions are known to be critical in maintaining local and systemic health of the human body, although they are difficult to study in both clinical and in vitro applications. Despite efforts, recapitulation of gingival architecture and physiological characteristics of the periodontal niche cannot be achieved by traditional tissue engineering strategies. Here, we advanced our humanized three-dimensional gingival model by co-culturing it with a healthy patient-derived microbiomes for seven days within an oral bioreactor that mimics native salivary dynamics. Our results indicated long-term host and microbiome viability, host barrier integrity and physiological response, and preservation of healthy microbial populations and interbacterial dialogues. The model has proven useful in successfully mimicking tissue homeostasis at the interface of the periodontal niche and suitable for the introduction of immune cells. Future studies will focus on using the model as a comparator of periodontal inflammation and identifying biomarkers associated with eubiotic/dysbiotic profiles. Graphical Abstract Created partially in biorender.com.
... As cytokines have involved in the pathogenesis of a various inflammatory diseases, they are attractive therapeutic targets in these conditions (45,46) . Some studies have evidenced the therapeutic benefit of targeting IL -1β and IL -37 to improve the inflammatory response in inflammatory diseases (20,30,42,47) . Therefore, we examined the effect of rIL -37 on P -OMVs stimulated DGFs. ...
... Chronic inflammation is the result of an imbalance between proand antiinflammatory mechanisms(16,17) . IL -1 family members are primary signaling molecules that advance periodontal inflammation(30) . The IL -1 family consists of eleven cytokines, with seven inducing proinflammatory responses(IL -1α, IL -1β, IL -18, IL -33, IL -36α, IL -36β, andIL -36γ) and four inducing antiproinflammatory responses [IL -1 receptor antagonist (Ra) , IL -36Ra, IL -37, andFig. ...
Article
Individuals with Down syndrome(DS)are prone to periodontitis. No studies have focused on mRNA expression of a pro-inflammatory cytokine, IL-1β and an anti-inflam matory cytokine, IL-37 in gingival fibroblasts(GFs)derived from individuals with DS (DGFs). We cultured GFs derived from non-DS individuals(NGFs)and DGFs with outer membrane vesicles from Porphyromonas gingivalis(P-OMVs). IL-1β and IL-37 mRNA expression was quantified using real-time PCR. Extracellular signal-regulated kinase(ERK)1/2 phosphorylation was performed by western blotting. We also analyzed the effect of an ERK1/2 inhibitor on IL-1β and IL-37 mRNA expression in GFs. Furthermore, we examined the influence of recombinant IL-37(rIL-37)on the cellular response of GFs. We quantified mRNA expression of IL-8 using real-time PCR and measured IL-8 productions in culture medium by an enzyme-linked immunosorbent assay. IL-1β mRNA expression and phosphorylated-ERK1/2 expression were significantly higher in P-OMVs-stimulated DGFs than in NGFs. In contrast, IL-37 mRNA expression was significantly lower in P-OMV-stimulated DGFs than in NGFs. P-OMVs-induced IL-1β and IL-37 mRNA expression in NGFs was reduced by an ERK1/2 inhibitor, while P-OMVs-induced IL-37 mRNA expression was not reduced by an ERK1/2 inhibitor in DGFs. P-OMVs-induced IL-8 mRNA expression and protein production were decreased by rIL-37 in both NGF and DGFs. It is considered that the imbalance of pro- and anti-inflammatory responses via ERK1/2 in DGFs may cause severe periodontal inflammation in DS. In addition, IL-37 may be a key mediator of the anti-inflammatory response in DGFs. These results provide insights into the therapeutic potential of targeting anti-inflammatory factors for severe periodontal inflammation in DS.
... The role of IL-33 in periodontitis remains controversial. IL-33 and ST2 expression are increased in periodontic regions in both humans and mice (Malcolm et al., 2015;Lapérine et al., 2016;Tada et al., 2016), apparently reflecting enhanced expression by oral epithelial cells (Tada et al., 2017;Papathanasiou et al., 2020). In vitro, IL-33 promotes osteoclast (OC) differentiation from human monocytes and peripheral blood mononuclear cells, even in the absence of receptor activator of nuclear factor kappa-B ligand (RANKL) (an OC differentiation factor) (Mun et al., 2010;Eeles et al., 2015). ...
... Thus, the role played by IL-33 in periodontitis remains controversial and may differ among models. Using a bacteria-free, ligature-induced periodontitis model, we found that alveolar bone loss was re- (Tada et al., 2017;Papathanasiou et al., 2020). IL-33 is also inducible on myeloid cells, such as macrophages and neutrophils, under pathological conditions such as the microbial response (Ohno et al., 2012). ...
Article
Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been studied primarily in the context of type 2 immune responses. Recent reports suggest that IL-33 also enhances the func- tions of various immune cells and contributes to the development of different inflammatory diseas- es. Interestingly, IL-33 and its receptor ST2 axis exerted either inhibitory or promotional effects on alveolar bone loss in various periodontitis models. Using a mouse model of ligature-induced periodontitis, we found that the levels of mRNAs encoding IL-33 and other inflammatory cyto- kines (IL-1α, IL-1β, IL-6, and TNFα) were augmented in gingival tissues of wild-type (WT) mice, and that the alveolar bone loss amount was lower in IL-33-deficient than WT mice. The numbers and proportions of IFN-γ-producing CD8+ T and regulatory T cells were decreased while those of Th17 cells were increased in the draining lymph nodes of IL-33-deficient mice compared to WT mice. Additionally, the level of RNA encoding an osteoclastogenic molecule, i.e., receptor activa- tor of nuclear factor kappa-B ligand (RANKL), in ligated gingival tissue was higher in IL-33-defi- cient than WT mice. These results suggest that IL-33 is involved in alveolar bone loss in the ligature-induced periodontitis model, although IL-33 may inhibit osteoclast differentiation.
... These proinflammatory signals combined with bacterial products in the periodontal tissues in turn will stimulate both innate and adaptive immunity response. Hence, both complexes will promote release of inflammatory cell mediators into the periodontium (Papathanasiou et al., 2020). Virulence properties of periodontal pathogens such as lipopolysaccharides, stimulates the release of both IL-1α and IL-1β form oral epithelial cells hence resulting in periodontal destruction. ...
... However, IL-1 family members possessing anti-inflammatory properties play a defence role in periodontitis. Here, they will alleviate the magnitude of periodontal inflammation (Papathanasiou et al., 2020). The production of PGE 2 by the immune cells, fibroblasts and other resident gingival cells is associated with the formation of osteoclast via RANKL upregulation and osteoprotegerin (OPG) inhibition (Belibasakis & Guggenheim 2011). ...
Article
Full-text available
Periodontitis is an oral inflammatory process involving the periodontium, which is mainly caused by the invasion of periodontopathogenic microorganisms that results in gingival connective tissue and alveolar bone destruction. Metabolic products of the oral pathogens and the associated host immune and inflammatory responses triggered are responsible for the local tissue destruction. Numerous studies in the past decades have demonstrated that natural polyphenols are capable of modulating the host inflammatory responses by targeting multiple inflammatory components. The proposed mechanism by which polyphenolic compounds exert their great potential is by regulating the immune cell, proinflammatory cytokines synthesis and gene expression. However, due to its low absorption and bioavailability, the beneficial effects of these substances are very limited and it hampers their use as a therapeutic agent. To address these limitations, targeted delivery systems by nanoencapsulation techniques have been explored in recent years. Nanoencapsulation of polyphenolic compounds with different carriers is an efficient and promising approach to boost their bioavailability, increase the efficiency and reduce the degradability of natural polyphenols. In this review, we focus on the effects of different polyphenolic substances in periodontal inflammation and to explore the pharmaceutical significance of polyphenol-loaded nanoparticles in controlling periodontitis, which may be useful for further enhancement of their efficacy as therapeutic agents for periodontal disease.
... Bacterial virulence factors such as LPS and leukotoxin have been shown to attack oral epithelial cells, triggering the release of proinflammatory factors interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β), which play a crucial role in periodontal destruction. 68 Autophagy acts to eliminate pathogens and inhibit the production of inflammatory factors, thereby mitigating inflammatory responses. 69 It is conceivable that IL1β may intensify inflammation in periodontal tissues by influencing the activity of the autophagy pathway. ...
Article
Full-text available
Objective Autophagy plays a crucial role in the pathophysiology of periodontitis, yet its precise involvement in the disease process remains elusive. The aim of the present study was thus to investigate the involvement of autophagy in the pathology of periodontitis. This investigation involved transcriptomic analysis of a broad range of human samples and complemented by in vitro experimentation. Materials and Methods We analyzed the transcriptomes of human gingival tissues from individuals with periodontitis and health controls to identify the differential expression of autophagy-related genes (DEARGs) and to investigate their potential interactions and functional pathways. Additionally, protein-protein interaction (PPI) networks were constructed to identify key functional modules and hub genes. Experimental validation of autophagy regulation in periodontitis and identification of key autophagy-regulating genes was accomplished through in vitro cellular experiments. Subsequently, a comprehensive analysis of immune cell infiltrate utilizing the CIBERSORT algorithm was performed. Finally, leveraging the DSigDB database, potential candidate drugs for periodontitis treatment targeting autophagy were predicted. Results A total of 79 genes have been identified as DEARGs in periodontitis. An intricate interplay among the DEARGs and their impact on the regulatory mechanisms of autophagy within the context of periodontitis was observed. Subsequently, 10 hub genes were discerned through the establishment of a PPI network. Furthermore, dysregulated autophagic activity in periodontitis was validated, and 9 key genes (APP, KDR, IL1B, CXCL12, CXCR4, IL6, FOS, LCK, and SHC1) were identified through in vitro experiments. Our analysis unveiled an association between these genes and altered immune cell infiltration in periodontitis. Additionally, we predicted potential therapeutic agents such as curcumin, 27-hydroxycholesterol, and Trolox, showing promise in the treatment of periodontitis by modulating the autophagic process. Conclusion This study identified nine key genes for autophagy regulation and potential therapeutic agents in periodontitis. These findings not only enhance our comprehension of the pathological mechanisms of periodontitis but also provide substantial evidence for the advancement of novel therapeutic strategies.
... However, for patients with periodontitis, under the long-term inflammatory microenvironment, the function of the PDL is affected and destroyed, resulting in a significant loss of periodontal support tissue [5]. The inflammatory microenvironment can stimulate the secretion of proinflammatory cytokines (such as interleukin (IL)-1β, IL-6, IL-8, etc.) [6][7][8], the production of these proinflammatory cytokines can cause further periodontal tissue damage, and studies have shown that PDLSCs derived from inflammatory tissues have increased proliferation ability compared to PDLSCs derived from healthy tissues, but decreased osteogenic differentiation ability [9]. Therefore, how to restore the biological function of PDLSCs under long-term inflammatory stimulation has become a hot topic in the treatment of periodontal disease. ...
Article
Full-text available
Transient receptor potential ankyrin 1 (TRPA1) molecule is an important type of transient receptor potential (TRP) cation channels, which can cause extracellular Ca²⁺ to flow into cells after activation. TRPA1 plays an important role in acute and chronic pain, inflammation, kidney disease, cough and asthma, osteoarthritis, cardiovascular disease, obesity, diabetes, and other diseases. In this study, the expression of interleukin (IL)-1β, IL-6, and IL-8 in periodontal ligament stem cells (PDLSCs) treated by lipopolysaccharide (LPS) and the effect of LPS on PDLSCS proliferation were detected. Meanwhile, the change in TRPA1 expression in PDLSCs treated by LPS was also assessed. By knocking down the expression of TRPA1 and using the TRPA1 antagonist HC-030031, the expression of IL-1β, IL-6, and IL-8 in PDLSCs treated by LPS was downregulated. After LPS stimulation, the proliferation ability of PDLSCs decreased, the gene expression and secretion of IL-1β, IL-6, and IL-8 increased and the gene and protein expression of TRPA1 were upregulated. Reducing the expression of TRPA1 can effectively inhibit the increase of gene expression of IL-1β, IL-6, and IL-8 after LPS stimulation, and pretreatment of PDLSCs with HC-030031 can also achieve the above effect. And research has found that HC-030031 can inhibit the phosphorylation level of JNK in PDLSCs treated by LPS. The use of JNK inhibitor JNK-IN-8 can also reduce the expression of IL-1β, IL-6, and IL-8 in PDLSCs. Finally, this study found LPS could cause the upregulation of TRPA1, and the inhibition of TRPA1 could produce an anti-inflammatory effect in PDLSCs treated by LPS due to its inhibition of JNK phosphorylation.
... Two of the IL-1 members are IL-1α and IL-1β. IL-1α initiates and maintains the inflammatory process in periodontal tissue ( 65 ), while IL-1β functions in responding to other inflammatory cytokines, notably TNF-α, which is the main mediator of periodontal inflammation and bone destruction ( 66 ), as well as increasing the regulation of MMP-9 expression and PGE2 synthesis in fibroblast cells ( 65,67 ). Surprisingly, several papers found curcumin significantly reduced TNF-α expression ( 36,37,40,46,49,50 ), where TNF-α is the pro-inflammatory cytokine that contributes to periodontitis-related bone resorption, and correlates with PGE2 biosynthesis ( 68,69 ). ...
Article
Full-text available
Introduction There is ongoing exploration into herbal treatments to identify adjunct therapies with minimal side effects. One such treatment involves curcumin from turmeric (Curcuma longa). This study aims to review the efficacy of curcumin as an anti-inflammatory agent for periodontitis along with the mechanisms of action involved. Methods A systematic review of pre-clinical and clinical studies published on Scopus, PubMed, ScienceDirect, and Google Scholar up to May 2024 was employed following the PRISMA guidelines. Three tools were used for risk of bias assessment, namely the QUIN tool for in vitro studies, the SYRCLE’s RoB for in vivo studies, and the Cochrane RoB 2 for RCTs. Finally, nineteen studies were included for review. Results This study highlights curcumin’s efficacy in addressing periodontitis through diverse mechanisms. Curcumin demonstrated efficacy in attenuating inflammation within periodontal tissue by inhibiting several pro-inflammatory cytokines and mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, matrix metalloproteinases (MMPs), prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, while concurrently increasing IL-4 and IL-10. In addition, several transcription factors such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 1 (STAT1) were also inhibited by curcumin. Administration of curcumin has additionally been demonstrated to reduce other biomarkers of periodontitis, including C-reactive protein (CRP), alkaline phosphatase (ALP), and procalcitonin (PCT). Conclusion Curcumin has been shown to be effective as an adjunct therapeutic agent for periodontitis due to its anti-inflammatory effects by reducing the inflammatory response through a diverse range of mechanisms of action.
... Stages of endometriosis development [14][15][16] An important role in the pathogenesis of endometriosis is attributed to the interleukin-1 family. Interleukins belonging to the IL-1 family play an important role in the regulation of the immune and inflammatory response, affecting almost all types of cells [17]. The interleukin-1 family consists of 11 proteins, including 7 pro-inflammatory agonists (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and 4 anti-inflammatory antagonists (IL-1Ra, IL-36Ra, IL-37 and IL-38) [18,19]. ...
Article
Objectives: Endometriosis is a complex, chronic inflammatory disease in which immune system disorders play an important role. Soluble mediators of the immune and inflammatory response, including cytokines, are involved in these processes. Therefore, the aim of the conducted research was to understand the role of selected cytokines belonging to the Interleukin-1(IL-1) family, including IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38, in the onset and development of endometriosis by analysing the concentration of the tested molecules and to determine whether their concentration depends on the stage of the disease. Material and methods: The study group included 60 women who had pelvic endometriosis diagnosed during laparoscopy and subsequently confirmed by histopathology. The reference group consisted of 20 women who had no endometriosis or other pelvic lesions during laparoscopy. Results: Immunoenzymatic assays were used to determine the concentration of the cytokines studied. In the peritoneal fluid of women with endometriosis, a statistically significant increase in the concentrations of all parameters tested was observed: IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38. The concentration of these cytokines depended on the severity of the disease. Conclusions: Disturbances of the immune system involving the network of cytokines belonging to the IL-1 family occurring in the peritoneal fluid environment testify to the involvement of these molecules in the development of the disease and are one of many factors involved in the pathogenesis of endometriosis. The use of some of them in the treatment of endometriosis may be a hope for effective causal treatment of this disease, but this requires further, more advanced research.
... Fibroblasts are the dominant cells in the proliferation phase, forming new connective tissue and synthesizing collagen which affects tensile strength in tissue rejuvenation (Hanna and Giacopelli, 1997). Dysbiosis can impair periodontal tissue homeostasis by causing an imbalance within the microbial ecosystem, resulting in a significant production of Interleukin (IL)-1 members and initiating an over immune response via host receptors (Jia et al., 2019;Papathanasiou et al., 2020). Cellular immune responses show the role of various cytokines in the process of inflammation of periodontal tissue (periodontitis). ...
Article
Full-text available
Background Gingivitis is a dysbiotic condition characterized by persistent inflammation caused by a disease-associated multispecies bacterial population that has established itself in the subgingival region. Aim The objectives of this study are to analyze the anti-inflammatory activity of sappan wood extract cream (SWC) in Porphyromonas gingivalis induced-periodontitis rats model. Methods In this study, rats were infected with the gingiva with P. gingivalis as an inducer for gingivitis rats model for 14 days. The SWC were treated topically into the infected tissue. The inflammation and angiogenesis of gingival tissue was analyzed using histological examination. An immunohistochemistry (IHC) assay was used to analyze the nuclear factor kappa-B (NF-kB) protein expression. Masson Trichrome (MT) assay was used to analyze the histopathology of collagen Scores. The tumor necrosis factor-α (TNF-α), Interleukin-1 β (IL-1β), IL-6, and P38 genes expression were measured using quantitative real time-polymerase chain reaction. Results The induction of P. gingivalis-induced gingivitis in rats model was indicated by reddish gingiva and bacterial plaque. MT tests showed that SWC increased collagen density, and Haematoxylin and Eosin (H&E) test showed increased angiogenesis and in contrast, lowered inflammation score. IHC test showed that SWC decreased the expression of NF-kB protein. The TNF-α, IL-1β, IL-6, and P38 gene expression were also decreased due to the SWC treatment. Conclusion SWC proves that it has anti-inflammatory activity which has the potential to prevent or treat gingivitis.
... Both the diagnosis and treatment of periodontitis are well established, however, there are still gaps in knowledge about the molecular mechanisms involved in the regulation of the inflammatory and destructive process of the periodontium, therefore, knowing these aspects will greatly facilitate scientists and clinicians in precision treatment [4]. or alarmin is a proinflammatory cytokine, a member of the IL-1 family, which plays an important role in human inflammation and in particular in the periodontal immune response [5]. IL-33 is encoded by the IL33 gene located on 9p24.1 [6]. ...
Article
Full-text available
Background Activation of the IL-33/ST2 axis leads to the production of proinflammatory cytokines and thus to the triggering of osteoclastogenesis, which is why it plays an important role in the immunopathogenesis of periodontitis. The aim of this study was to compare IL-33 levels in serum, plasma, saliva and gingival crevicular fluid (GCF) of subjects with chronic periodontitis (CP) in comparison with the control group (CG). Methods This systematic review and meta-analysis followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and was registered in the Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/YHUWA. Six electronic databases were used for study identification; PubMed, Google Scholar, ScienceDirect, Web of Science, Scopus and Dentistry & Oral Sciences Source from March 10, 2012 to April 30, 2024. The Joanna Briggs Institute (JBI) tool was used to assess the quality of the included cross-sectional articles and clinical trials. Results Of the 949 articles identified, 14 were included according to the inclusion and exclusion criteria. The total number of individuals studied in the included investigations was 814 of whom 445 had CP and 369 were healthy. The reported age range was from 20 to 50 years, with a mean age ± standard deviation of 40.29 ± 7.83 years. Four hundred and twenty-six (52%) patients were men and 388 (48%) were women. Meta-analysis revealed that there is an increase in IL-33 levels in plasma, saliva and GCF of subjects with CP compared to CG (p = * < 0.05). Conclusions This study found a significant increase in IL-33 levels in different biological samples (plasma, saliva and GCF) of individuals with CP compared to CG, thus IL-33 has potential to be a biomarker in the diagnosis of periodontitis.
... In this study, we assessed both saliva and GCF as crucial oral secretions that can provide valuable insights into the impact of systemic and local diseases. Among the cytokines evaluated in periodontal diseases, IL-1β was of particular interest due to its well-established association with bone resorption [25]. Interestingly, the levels of salivary IL-1β were found to be significantly higher in the BG group compared to HG group. ...
Article
Full-text available
Aim This study explores the connection between Behçet’s disease (BD), characterized by persistent oral and genital ulcers alongside iritis, and periodontal disease. It examines the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in gingival crevicular fluid (GCF) and saliva. Methods Forty Behçet’s patients with gingivitis or periodontitis and 47 patients with either gingivitis or periodontitis but without BD were studied. Periodontal status was recorded with standard clinical indexes. GCF and saliva samples were obtained. NO, IL-1β and TNF-α levels were analysed. Current Behçet’s symptoms and medications usage were recorded. Results Mean salivary IL-1β was elevated (p = .045), and mean NO level was decreased in BD patients with gingivitis compared to patients without BD (p = .000). In contrast, mean NO level in crevicular fluid was higher in Behçet’s patients with periodontitis than in patients without BD (p = .009). Furthermore, among Behçet’s patients, those with vascular involvement had lower salivary NO level compared to patients without vascular involvement (p = .000). Conclusions Based on our findings, the elevated levels of IL-1β in the saliva of Behçet’s patients with gingivitis, along with the decreased NO level, indicate an altered inflammatory response in the oral cavity.
... Papathanasiou et al. [76] IL-1 family contains the major signaling molecules which stimulate and perpetuate periodontal inflammation. ...
Article
Full-text available
Periodontal disease (PD) is a chronic inflammatory disease with some cytokine involvement, associated with several risk factors such as diabetes, obesity, etc., Corona Virus Disease 2019 (COVID-19), a new viral infection, also appears to be related to cytokine storm and similar risk factors. In this review, we intend to evaluate the possible relationship between PD and COVID-19. For data collection, English literature was searched in databases including PubMed and Google Scholar. The keywords searched were COVID-19, SARS-CoV-2, PD, respiratory Impact of Oral pathogens on respiratory diseases: Epidemiological studies indicated that oral pathogens are related to acute and chronic lung disease, and dental plaque is a likely reservoir for respiratory pathogens. Viral presence in the periodontal pocket: SARS-CoV-2 may be released from infected periodontal cells into periodontal pockets. Common inflammatory mediators: Several studies showed that the serum levels of interleukins (IL)-1, 6, 17, etc., increase in most patients with severe COVID-19. C-reactive protein (CRP) and endothelin 1(ET-1) may also be related to COVID-19 progression, and these mediators also increase in periodontitis. Common risk factors: Due to studies, diabetes mellitus (DM), obesity, aging, and male sex are the most important risk factors common between PDs and COVID-19 and may affect treatment outcomes and prognosis. PD seems to play a significant role in exacerbating COVID-19 and even affects the mortality rate of disease.
... Periodontitis, the primary cause of tooth loss, has become a widespread public health problem and affects 42.2% of the population of US adults [1,2]. Periodontitis is caused by a periodontal pathogen and can lead to loss of soft tissue attachment and alveolar bone resorption [3]. ...
... However, among DAMPs, the interleukin (IL)-33/ST2 (encoded by Il1rl1) axis, which functions as a vital alarmin in various infectious diseases and is crucial for mucosal immunity, has not been extensively studied in periodontitis 31 . IL-33, unlike other members of the IL-1 superfamily, is continuously present in the nucleus of tissue component cells (especially epithelial cells), and released when cells reach the end of their life due to infection or trauma 32 . The IL-33 receptor is composed of the IL-1 receptor accessory protein (IL-1RAcP) and ST2, and ST2 not only acts as a binding site but also has a soluble decoy isoform (sST2, translated by different transcript variants from the same gene) that modulates signaling 31 . ...
Article
Full-text available
Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2⁻ fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss in the acute phase of periodontitis, along with macrophage polarization towards a classically activated phenotype and increased neutrophil infiltration, indicating a protective role of the IL-33/ST2 axis in acute inflammation. Thus, our findings highlight the hidden role of the peri-root tissue and simultaneously advance our understanding of the etiology of periodontitis via implicating the IL-33/ST2 axis.
... IL-1α and IL-1β polymorphisms were associated with gingivitis [44]. IL-1α and IL-1β are critical pro-inflammatory cytokines implicated in the development of PD [95]. Stimulated by a bacterial infection or inflammatory triggers in the oral cavity, these cytokines initiate a signaling cascade upon binding to their receptors [66]. ...
Article
Objectives: The present systematic review and meta-analysis aimed to assess the association between salivary protein polymorphisms and the risk of periodontal diseases (PD). Data: The review incorporated cross-sectional, case-control, retrospective/prospective cohort, and randomized controlled trials assessing the influence of salivary protein polymorphisms on the risk of PD development were included in this review. Sources: A thorough literature search was conducted across electronic databases, namely PubMed, Scopus, Embase, and Web of Science, without any restrictions on publication language and year. Study selection: A total of 168 studies were identified, of which 19 were eligible for inclusion. The risk of bias (RoB) assessment of the included studies was conducted at the methodological level. Results: A total of 16 studies were included. Polymorphism in the gene encoding TNF-α was found to be protective against gingivitis, while those encoding IL-1α and IL-1β were associated with developing gingivitis. Of the 42 proteins investigated, various gene polymorphisms were identified as protective or risk factors for periodontitis. Protective genes include CFH, DNMT1, OPRM1, and TLR9. Conversely, certain salivary protein genes (e.g., CRP, ERN1, FAM5C, IDH2, LTA, TET2, MPA, NLRP3, TLR4) were associated with periodontitis risk. Notably, IL6, MMP9, and MUC7 genes showed no association with PD, while MMP13 was linked to early implant loss. Overall, the meta-analysis found a statistically significant association between salivary proteins’ polymorphisms and risk of PD. Conclusions: Salivary protein polymorphisms significantly influence PD, revealing protective and risk-associated genotypes. Despite limitations, findings suggest therapeutic targets, emphasizing the complex genetics-periodontal health interplay. Clinical significance: This study unveils salivary protein polymorphisms as pivotal factors in PD. Protective genes including CFH and TLR9, and risk-associated genes including CRP and TLR4, indicate a genetic basis for PD susceptibility.
... exert anti-inflammatory properties by relieving IL-8 release and is related to the level of IL-1β [32,33]. Many studies have shown that periodontitis could be induced by pro-inflammatory cytokines, such as IL-1α, IL-1β, and TNF-α [34][35][36]. These cytokines influence osteoclasts' formation and absorption capacity in different ways, leading to bone resorption [37,38]. ...
Article
Full-text available
To explore the bacterial and inflammatory variations in oral cancer patients with and without jawbone invasion. A total of 20 specimens of fresh tumor tissue, including 10 from the tumor-invaded jawbone (JIOC group) and 10 without jawbone invasion (NJIOC group), were collected from oral cancer patients. Meanwhile, 10 specimens from normal oral mucosa were collected from healthy patients (control group). The microbiomic content of each sample was analyzed by 16S rRNA gene sequencing, while the expression of inflammatory cytokines was assessed using protein microarray analysis. There was a significant difference in β diversity between JIOC and NJIOC groups (P < 0.05), but no difference between NJIOC and control groups. The average relative abundance of Fusobacteria and Spirochaetes was higher, while Firmicutes was lower in the JIOC group than in the NJIOC group (all P < 0.05). The expression of pro-inflammatory cytokines like interleukin (IL)-1α, IL-1β, IL-4, and IL-8 was upregulated in the JIOC group compared with the NJIOC group, while MCP-1 was decreased (all P < 0.05). Slackia spp. and Howardella spp. were positively correlated with IL-4; Odoribacter spp. and Acidaminococcaceae spp. were negatively correlated with IL-4, and Clostridium XIVa spp. was negatively correlated with IL-1α and IL-1β. Bacterial and inflammatory differences were observed in oral cancer patients with and without jawbone invasion, where the relative abundance of the differential bacteria was associated with the expression of the inflammatory cytokines. This study investigated the changes in the flora during jawbone invasion in oral cancer and its effect on inflammatory factors, elucidating the possible mechanisms of jawbone invasion caused by oral cancer, which may lead to new ideas for the clinical prevention and treatment of jawbone invasion in oral cancer.
... Certainly, the development of periodontal disease is indeed connected to a localized inflammatory response and the activation of the immune system triggered by bacterial components [37]. This process heavily relies on the stimulation of pro-inflammatory molecules and the activation of cytokine networks, particularly interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) [38]. Conversely, autoimmune-inflammatory mechanisms are also pivotal in the development of most diseases associated with DG, often involving shared cytokine molecules/networks (for example, TNF-α in the case of OLP) [18,39]. ...
Article
Full-text available
Desquamative gingivitis is a clinical condition with a chronic course, not specific to a particular disease, characterized by intense erythema, scaling, vesicles, and/or blisters that may involve both the marginal free gingiva (MG) and the neighboring adherent gingiva (AG). This scoping review aimed to investigate whether there is a correlation between oral hygiene and gingival lesions induced by autoimmune diseases of the oral cavity and whether periodontal disease can negatively influence a clinical picture of desquamative gingivitis due to an immune disorder of the oral cavity. Case series studies and randomized controlled trials were considered for this scoping review; studies that did not comply with the inclusion criteria were excluded. A total of seven studies were selected for this review. The PRISMA-ScR (preferred reporting items for scoping reviews) consensus has been followed. Based on the included studies, it is possible to state that improvement in disease and patient-reported outcomes may be the result of appropriate oral hygiene education when patients are found to have autoimmune diseases with gingival manifestations.
... A neurogenic mechanism involving natural killer 1 receptors activates PAR-2 in the temporomandibular joint, causing inflammation [29]. Periodontal inflammation is triggered and perpetuated by signaling molecules belonging to the interleukin (IL)-1 family [30], and IL-1 receptor 1 was associated with anterior disc displacement with reduction (ADDwR) and anterior disc displacement without reduction (ADDwoR) in TMD discs of humans [31]. ...
Article
Full-text available
Background Periodontitis (PD) may affect temporomandibular joint disorders (TMD) and TMD may influence PD in previous observational studies. Nevertheless, these studies were prone to confounders and reverse causation, leading to incorrect conclusions about causality and direction of association. This research investigates the associations between PD and TMD employing bidirectional two-sample Mendelian randomization (MR) analysis. Methods Single-nucleotide polymorphisms (SNPs) related to PD (p < 5 × 10⁻⁶) were selected from a genome-wide association study (GWAS) from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) consortium, and related these to SNPs from FinnGen and UK Biobank (UKB) consortia, and vice versa. We implemented the standard inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, and MR-PRESSO methods to estimate the potential causality between PD and TMD. Sensitive tests were conducted using robust MR methods. Results from FinnGen and UKB were combined using the fixed model. Results PD did not appear to causally affect TMD. Additionally, the reverse MR analysis did not reveal a significant causal effect of TMD on PD. The results of other MR methods were similar to those of the IVW method. Sensitivity analyses addressed no potential pleiotropy in MR estimations. Results from the meta-analysis were consistent with the above-mentioned consequences. Conclusion This research does not support a causal relationship between PD and TMD. PD does not appear to worsen TMD directly, and vice versa.
... Periodontitis is a chronic inflammatory condition resulting from the actions of multiple causes that leads to microenvironmental changes in the tooth-supporting tissues and is exacerbated by a further dysbiosis of the microbial biofilm that deepens the inflammatory response [74]. The bacteria in this biofilm release numerous virulence factors, including lipopolysaccharides and antigens, which activate cytokines, chemokines, and transcription factors that may contribute to connective tissue destruction and bone resorption [75]. The standard treatment combines professional biofilm with a personalized at-home hygiene program. ...
Article
Full-text available
Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.
... Periodontitis, the destruction of tooth-supporting tissue, is a complex and multifactorial infectious inflammatory disease involving interactions between bacteria, inflammatory responses, host immunity, genetics, and environmental factors. 1,2 Therefore, in addition to anti-infection control, host response modulation might be the other alternative approach. For instance, to control multidrug-resistant tuberculosis, host-directed therapy, aimed at improving innate or adaptive protective immune response to control pathogens and/or limit immunopathology, was proposed. ...
Article
Full-text available
Background/purpose Probiotics might be beneficial in preventing periodontitis. Effects of Bifidobacterium and Lactobacillus on periodontitis were examined using the ligature-induced rat model. Materials and methods Thirty-five male Sprague-Dawley rats were divided into control, ligation, Bifidobacterium longum (BL986), Lactobacillus rhamnosus (LRH09), and combination groups. Periodontitis was induced in maxillary second molars. From the day before ligation, phosphate-buffered saline (for control and ligation groups) or probiotics (2 × 10⁹ CFU/g for probiotic groups) were fed daily. On day 8, gingival mRNA expressions for interleukin (IL)-1β, IL-6, tissue necrosis factor (TNF)-α, IL-10, and NF-κB were determined via qPCR. Micro-computed tomography (μCT) and histomorphometry were employed to examine periodontal destruction. Results Compared to the ligation group, mRNA of IL-1β, TNF-α, IL-6, and NF-κB in probiotic groups were significantly decreased, but IL-10 was increased. Besides, the IL-10 was more significant in the combination group than in single-use group. Through μCT, the cementoenamel junction (CEJ)-to-bone distance and trabecular separation in combination group were less than that in ligation group, although the bone volume fraction and trabecular number/thickness showed an increase in three probiotic groups. Histopathologically, the combination group had significantly smaller gingival inflammatory cell-infiltrated area and CEJ-to-epithelium distance than the ligation group and the group with BL986 or LRH09. Additionally, the CEJ-to-bone distance was significantly smaller in the combination group than in the ligation and BL986 groups. Conclusion Systemic combination of BL986 and LRH09 had a synergistic effect on enhancing IL-10 and ameliorating the induced experimental periodontitis, although the single-use still presented partially alleviative effects.
... In patients with T 2 DM and chronic periodontitis, some studies showed an increased level of IL-1ß in the gingival crevicular fluid. At the same time, other published data did not report statistically significant differences compared to people with only one of the two diseases [94,96]. ...
Article
Full-text available
Periodontitis is a chronic inflammatory disease caused by the presence of a bacterial biofilm known as dental plaque. This biofilm affects the supporting apparatus of the teeth, especially the periodontal ligaments and the bone surrounding the teeth. Periodontal disease and diabetes seem to be interrelated and in a bidirectional relationship, and have been increasingly studied in recent decades. For example, diabetes mellitus has a detrimental effect on periodontal disease, increasing its prevalence, extent, and severity. In turn, periodontitis negatively affects glycemic control and the course of diabetes. This review aims to present the most recently discovered factors that contribute to the pathogenesis, therapy, and prophylaxis of these two diseases. Specifically, the article focuses on microvascular complications, oral microbiota, pro- and anti-inflammatory factors in diabetes, and periodontal disease. As presented in this review, these two diseases require specific/ complementary therapeutic solutions when they occur in association, with new clinical trials and epidemiological research being necessary for better control of this interdependent pathogenic topic.
... It is encoded by the IL1B gene and was initially discovered as the major endogenous pyrogen. It is produced by monocytes/macrophages, dendritic cells [120], gingival fibroblasts, periodontal ligament cells and osteoblasts. Its production has been increased and altered in multiple inflammatory disorders, mainly rheumatoid arthritis, cryopyrin-associated periodic syndrome (CASP), gout, type II diabetes mellitus, as well as in periodontitis [121,122]. ...
Article
Full-text available
The success of a prosthetic treatment is closely related to the periodontal health of the individual. The aim of this article was to review and present the importance of prosthetic restorative materials on the condition of the periodontium, the changes that occur in the composition of the subgingival microbiota and the levels of inflammatory markers in gingival crevicular fluid. Articles on the influence of different prosthetic restorative materials on subgingival microbiota and proinflam-matory cytokines were searched for using the keywords "prosthetic biomaterials", "fixed prosthesis", "periodontal health", "subgingival microbiota", "periodontal biomarkers" and "gingival crevicular fluid" in PubMed/Medline, Science Direct, Scopus and Google Scholar. The type of material used for prosthesis fabrication together with poor marginal and internal fit can result in changes in the composition of the subgingival microbiota, as well as increased accumulation and retention of den-tobacterial plaque, thus favoring the development of periodontal disease and prosthetic treatment failure. Biological markers have helped to understand the inflammatory response of different pros-thetic materials on periodontal tissues with the main purpose of improving their clinical application in patients who need them. Metal-free ceramic prostheses induce a lower inflammatory response regardless of the fabrication method; however, the use of CAD/CAM systems is recommended for their fabrication. In addition, it is presumed that metal-ceramic prostheses cause changes in the composition of the subgingival microbiota producing a more dysbiotic biofilm with a higher prevalence of periodontopathogenic bacteria, which may further favor periodontal deterioration.
... Basheer et al. [54] proved the sleep deprivation could active the transcription factor -NF-κB, suggesting the possibility of transcriptional activation of genes regulated by NF-κB, like IL-1β, TNF-α, nitric oxide synthase (NOS), cyclooxygenase (COX)-2 . The expressions of these target genes may increase the risk of periodontitis [55][56][57]. ...
Article
Full-text available
PurposePeriodontitis is a chronic inflammatory disease caused by multi-factors. Sleep is a natural physiologic process, and the sleep duration, quality, and patterns might be associated with periodontitis. Meanwhile, periodontitis might in turn induce systemic inflammation and thus impact sleep in different ways as well.Methods To investigate the bidirectional relationship between sleep disorder and periodontitis, a literature search was conducted to reveal the interaction and possible mechanism between these two diseases.ResultsThe results show that sleep disorders can affect the progression of periodontitis via some pathomechanisms, and periodontitis also has a reverse impact on sleep.Conclusion Although the epidemiologic and clinical trials found the possible associations between sleep disorder and periodontitis, their relationship is still not that explicit. Further studies are warranted to shed light on them, to improve preventive health care.
... Immune response imbalance is a complex component of periodontitis pathogenesis [20]. Several cytokines including IL-1, TNF-α, IL-6, IL-8, IL-10, IL-17, and IL-33 are involved in the pathogenesis of periodontal disease by regulating the interactions and cellular networks among host defense cells [20][21][22][23][24]. Interleukin-1 is the major pro-inflammatory cytokine involved in the pathogenesis of periodontal disease and it has previously been demonstrated that increased levels of IL-1α and IL-1β in GCF are closely related to periodontal disease severity [25,26]. ...
Article
Full-text available
Objectives Familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) are chronic inflammatory diseases and anti-inflammatory agents are used in their treatment. This study evaluates the periodontal status and cytokine response in pediatric patients with FMF or sJIA.Materials and methodsForty-eight FMF/sJIA patients were under treatment/control and in attack-free period; 20 systemically healthy children participated in the study. FMF/sJIA patients were divided into two subgroups based on the treatment they received: receiving anti-IL-1 therapy (anti-IL-1 ( +)) and not receiving anti-IL-1 therapy (anti-IL-1 ( −)). The clinical periodontal indices were recorded. Gingival crevicular fluid (GCF) and serum samples were collected. Cytokine levels (IL-1β, IL-1α, TNF-α, IL-6, IL-8, IL-10, IL-17, IL-33) in GCF and serum were measured using ELISA kits.ResultsThere was no significant difference between the groups in terms of GCF IL-1β and IL-1α levels although, BoP and GI were significantly lower in the anti-IL-1 ( +) group compared to the control group. GCF IL-10 level was higher in the anti-IL-1 ( −) group than in the control group; GCF IL-8 levels were lower in both FMF/sJIA subgroups versus controls. There was no significant difference between serum cytokine levels of FMF/sJIA subgroups.Conclusions Considering the significant decrease in GI, BoP, and GCF IL-8 levels in the anti-IL-1 ( +) group, it can be concluded that anti-IL-1 medications may suppress periodontal inflammation clinically and immunologically.Clinical relevanceAnti-IL agents are not currently used in periodontal therapy. However, this study demonstrated the positive effect of anti-IL-1 medications on periodontal inflammation in pediatric patients with FMF or sJIA.
... 34 It was an important mediator of the inflammatory response and participated in a dynamic biological processes, such as cell proliferation, differentiation, and apoptosis. 35 IL1B was reported to induce ferroptosis by promoting the production of ROS, reducing the GXP4 level, and improving the MMP13 level in chondrocytes. 36 The role of IL1B in the development of periodontitis had been studied extensively. ...
Article
Full-text available
Objectives Periodontitis is a chronic inflammatory illness that may lead to tooth loosening and even loss, and its pathogenesis is not fully understood. Ferroptosis is an iron-dependent, regulated cell death. The present study aims to find the key ferroptosis-related genes (FRGs) in periodontitis and develop an mRNA-miRNA-lncRNA network to deeply explore the pathogenesis of periodontitis. Methods Data from the Gene Expression Omnibus (GEO) database and FerrDb database were downloaded to discover the differentially expressed mRNA, miRNA, and FRGs. Functional enrichment analysis was conducted for the differentially expressed FRGs (DE-FRGs), including gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein–protein interaction (PPI) network analysis. Targetscan and miRtarbase were used to estimate the miRNAs that DE-FRGs may interact with, whilst StarBase v3.0 was used for lncRNA-miRNA interaction. Results Seven DE-FRGs were identified through differential expression analysis. Interleukin 1 beta (IL1B) interacted with XBP1 and MMP13 in the PPI network. After taking the intersection between DE-miRNAs and predicted miRNAs, a ceRNA network containing IL1B, has-miR-185, has-miR-204, has-miR-211, has-miR-4306, and 28 lncRNAs was established. Conclusions Seven FRGs in periodontitis were identified, which might promote deeper understanding of ferroptosis in periodontitis.
Article
Inflammasomes are complex multimeric protein molecules that play a central role in orchestrating the inflammatory response within periodontal tissues. These structures, primarily located in immune cells like macrophages and dendritic cells, become activated when exposed to microbial pathogens which are commonly found in dental plaque. Inflammasomes, crucial regulators of inflammation, play a significant role in periodontal diseases. Activation of inflammasomes, particularly NOD-like receptor family, pyrin domain-containing 3, triggers the release of pro-inflammatory cytokines, exacerbating tissue destruction in the periodontium. The aim of this review is to comprehensively explore the role of inflammasomes in periodontology, elucidating their involvement in periodontal diseases, discussing the mechanisms of inflammasome activation, and evaluating their potential as therapeutic targets. A comprehensive search was conducted across three databases, namely PubMed, Medline, and Google Scholar, focusing on the role of inflammasomes in periodontology: Various search terms including inflammasome, periodontitis, inflammation, oral health, and related keywords were employed to identify relevant studies.
Article
Full-text available
Objective This article is aims to provide an overview of studies reported in the literature to investigate the etiological role of IL-1/IL-1ra in various disease conditions and the different drug delivery systems developed to achieve IL-1ra as a possible therapeutic option. Methods Studies reported in PubMed, Google scholar, and other open-source literature related to etiological involvement of IL-1ra in pathophysiological conditions and various drug delivery schemes developed for IL-1ra for its efficacy evaluation as a possible treatment for different disease conditions were surveyed. Results and conclusions The pathophysiological conditions involving IL-1/IL-1 ra spanned CNS-related disorders, Diabetes, Cardiac disorders, Ocular disease conditions, Gastrointestinal conditions, Tumor growth & metastasis, and miscellaneous conditions. The drug delivery systems developed for IL-1ra included a commercial drug product, Gene therapy, Antibody fusions, Extended-release delivery systems, and Pegylated-IL-1ra systems.
Article
Aim Porphyromonas gingivalis lipopolysaccharide ( Pg LPS) is a significant virulence factor and a driver of early innate immune responses in epithelial cells. The presence of Pg LPS in immediate proximity to gingival epithelium induces significant inflammatory responses. In primary human gingival keratinocytes (HGK), we utilized transcriptome analysis to elucidate the change in early gene expression induced by Pg LPS. Methods HGK cell cultures were treated with Pg LPS (4 h), and RNA was extracted and prepared for RNA sequence (RNAseq) analysis. Differentially expressed genes (DEGs) were identified, and potential interactions between these genes were subsequently examined using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analytic approaches to identify significantly enriched pathways. Expression of genes associated with relevant pathways was evaluated using real‐time quantitative reverse‐transcription polymerase chain reaction (RT‐qPCR). Results RNAseq analysis identified 25 DEGs, and GO and KEGG analytic approaches showed related genes expressed in two general pathways. First, pathways broadly related to urokinase and coagulation included the genes PLAU , PLAUR , and SerpinB2 . In RT‐qPCR analysis, these genes were induced by Pg LPS over time (4–24 h), and these data were consistent with Pg LPS induction of cell migration. Second, interleukin‐1 (IL‐1) receptor binding and cytokine‐activity pathways were also enriched. Genes associated with these pathways included IL36G , IL1B , IL1RN , and CXCL14 . RT‐qPCR analysis confirmed Pg LPS induction of genes associated with the IL‐1family. When expression of IL1B and IL36G genes was examined in relation to their respective antagonists, only IL36G gene expression was increased. CXCL14 gene expression was reduced over time, and this was consistent with RNAseq analysis. Conclusions Genes associated with significantly enriched GO and KEGG pathways are relevant to aspects of periodontal disease (PDD) pathogenesis. First, Pg LPS induced expression of PLAU , PLAUR , and SerpinB2 , and these changes were consistent with an increase in cell migration that was found. Second, both IL36G and IL1B gene expression was significantly induced, but only IL36G in relation to its selective antagonist ( IL36RN ) was increased. These data support that early upregulation of IL36G may serve as an alarmin that can drive early innate immune inflammatory responses in HGK. Further in vivo testing of these findings is ongoing.
Article
Background The aim of this study is to look into the clinical and biochemical outcomes of D 3 K 2 supplementation in addition to nonsurgical periodontal treatment (NSPT) for patients suffering from diabetes mellitus (DM) and periodontitis. Methods Thirty‐eight participants with DM and periodontitis were randomized into two different groups. The test group provided NSPT with D 3 K 2 whereas the control group received NSPT with placebo. Clinical periodontal parameters were recorded and serum and gingival crevicular fluid (GCF) were sampled at baseline and at the third and the sixth months after treatment. Glycated hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 25(OH)D 3 , parathyroid hormone (PTH), calcium (Ca) and magnesium (Mg) values were determined in blood samples. GCF and serum interleukin (IL)‐1β and IL‐10 levels were analyzed using enzyme‐linked immunosorbent assay. Results All clinical periodontal parameters were importantly decreased at the third and sixth months after treatment compared to baseline in both groups. At the sixth month, 25(OH)D 3 levels in the test group were observed to be statistically significantly higher than in the control group ( p = 0.02). Serum IL‐1β showed a statistically significant decrease at the sixth month compared to baseline and the third month in control group. Conclusion According to this study, there is limited additional benefit of D 3 K 2 given with NSPT in individuals with DM and periodontitis.
Article
Full-text available
Background Fixed dental prostheses (FDP) can affect the production of inflammatory cytokines causing damage to periodontal tissues. A systematic review and meta-analysis was carried out with the following two objectives: (1) to determine the prevalence and function of the different inflammatory cytokines present in gingival crevicular fluid (GCF) of teeth with metal–ceramic (M/C) and all-ceramic (A-Cs) prostheses, and (2) to analyze and compare the levels of inflammatory cytokines in GCF of teeth with M/C and A-Cs prostheses. Methods The protocol followed PRISMA and Cochrane guidelines and was registered in the OSF:10.17605/OSF.IO/RBHJU. A digital search was conducted in the databases PubMed/MEDLINE, Cochrane Library, Dentistry & Oral Sciences Source, Scopus, Web of Science, ScienceDirect, and Google Scholar, from July 15th, 2000 to March 1st, 2024. Study quality was assessed using the JBI tool for cross-sectional and longitudinal studies. A meta-analysis was performed using a random-effects model to evaluate the concentration of IL-1β in GCF of teeth with FDP of M/C and A-Cs. Results The search strategy provided a total of 8,172 articles, of which 14 investigations met the inclusion criteria. The total number of patients studied was 468 of whom 53% were women and the rest (47%) were men. The ages of the patients ranged from 19 to 73 years, with a mean age ± standard deviation (SD) of 38,5 ± 12,8 years. A total of 843 fixed dental prostheses were studied, of which 407 (48,27%) were M/C prostheses and 410 (48,63%) were A-Cs prostheses. We found that the levels of IL-1β, IL-1α, PGE2, NKA, CGRP, and CX3CL1 were increased in teeth with M/C prostheses compared to teeth with A-Cs prostheses. Meta-analysis revealed that there are no significant differences between IL-1β levels in GCF in teeth with M/C prostheses compared to teeth with A-Cs prostheses (SMD = 13.89 pg/ml (CI = −14.29–42.08), p = > 0.05). Conclusions A trend toward increased levels of inflammatory cytokines was found in GCF of teeth with M/C prostheses compared to teeth with A-Cs prostheses.
Article
Background Bacterial‐induced inflammation instigates the destruction of hard and soft tissues surrounding teeth in periodontitis. In severe cases, the increased number and activity of osteoclasts induces the resorption of alveolar bones, ultimately leading to tooth loss. Because of their diverse chemical structures and bioactivities, natural compounds are often suggested to treat a wide variety of diseases, including inflammatory disorders. Methods In the present study, we demonstrated an inhibitory effect of gossypetin, a hexahydroxy flavone, on osteoclast differentiation and bone resorption using in vitro culture of osteoclasts from mouse bone marrow macrophage (BMM) precursors and in vivo model of ligature‐induced periodontitis in mice. Results Gossypetin significantly reduced the differentiation of osteoclasts from mouse BMM precursors in the presence of the receptor activator of nuclear factor κB ligand (RANKL). In vitro, gossypetin inhibited critical signaling events downstream of RANKL including the auto‐amplification of nuclear factor of activated T‐cells, cytoplasmic 1, Ca ²⁺ oscillations, and the generation of reactive oxygen species. In a mouse ligature‐induced periodontitis model, the administration of gossypetin significantly reduced osteoclastogenesis and alveolar bone resorption. Furthermore, gossypetin prevented the ligature‐induced increase in macrophages and T cells and reduced the production of tumor necrosis factor‐α and interleukin‐6. Conclusion Taken together, these results show anti‐osteoclastogenic and anti‐inflammatory effects of gossypetin, suggesting the potential use of this natural compound in periodontitis.
Article
Background Gingivitis is an inflammation of the gums that is the initial cause of the development of periodontal disease by the activity of Nuclear Factor-kappa B (NF-κB), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), p38, and Tumor Necrosis Factor-α (TNF-α). Unaddressed chronic inflammation can lead to persistent disturbances in other parts of the body. Brazilin is a naturally occurring plant chemical that may have antibacterial and anti-inflammatory effects. Treatment based on the natural plant compound, brazilin, is developed in the form of a topical cream for easy application. Objective The aim is to develop the natural compound brazilin in the form of a topical cream as an anti-inflammatory agent to reduce NF-κB expression through Imunohistochemistry (IHC) methods, and the expression of pro-inflammatory genes IL-1β, IL-6, p38, and TNF-α. Methods Male Sprague-Dawley rats were induced with gingivitis using P. gingivalis bacteria. The observed groups included rats treated with a single application of brazilin cream and rats treated with two applications of brazilin cream. The treatment was administered for 15 days. On days 3, 6, 9, 12, and 15, anatomical wound observations and wound histology using hematoxylin-eosin and Masson’s Trichrome staining were performed. NF-κB protein expression was analyzed using the IHC method. Gingival inflammation gene expression of NF-κB, IL-1β, IL-6, p38, and TNF-α was measured using q-RTPCR. Results Single and double applications of brazilin cream increased angiogenesis and decreased NF-κB protein expression, in addition to the IL-1β, IL-6, p38, and TNF-α gene expressions. Conclusion In a rat gingivitis model, Brazilin cream may function as an anti-inflammatory agent in the gingival tissue.
Article
Background: The study aimed to analyze cytokine levels, including interleukin (IL)-1β, IL-10, and IL-36γ, to investigate the link between pro- and anti-inflammatory responses in periodontal conditions and assess their potential as diagnostic biomarkers for distinguishing between different types of periodontal conditions. Methods: 80 systemically healthy non-smokers (25 periodontally healthy, 25 with gingivitis, 30 with periodontitis) were included. Clinical periodontal parameters were recorded, and gingival crevicular fluid (GCF) samples were obtained. Receiver operating characteristic (ROC) curve analysis was applied to determine the diagnostic value of cytokines. Results: IL-36γ had the highest sensitivity for diagnosing periodontitis, although its specificity for identifying those without periodontitis was relatively low. The combination of IL-1β and IL-36γ was the most effective in differentiating periodontitis from periodontal health. IL-10 was found to be an acceptable discriminator for distinguishing gingivitis from healthy conditions. However, its sensitivity and specificity for identifying gingivitis were lower. The combination of the three cytokines showed the highest ability to distinguish between periodontitis and gingivitis. Conclusion: The levels of IL-1β, IL-10, and IL-36γ in GCF may provide insights into periodontal health and disease status. Further studies are needed to validate these results and explore the potential of these cytokines in periodontal disease management.
Article
Full-text available
Periodontitis is a chronic inflammatory disease caused by the local microbiome and the host immune response, resulting in periodontal structure damage and even tooth loss. Scaling and root planning combined with antibiotics are the conventional means of nonsurgical treatment of periodontitis, but they are insufficient to fully heal periodontitis due to intractable bacterial attachment and drug resistance. Novel and effective therapeutic options in clinical drug therapy remain scarce. Nanotherapeutics achieve stable cell targeting, oral retention and smart release by great flexibility in changing the chemical composition or physical characteristics of nanoparticles. Meanwhile, the protectiveness and high surface area to volume ratio of nanoparticles enable high drug loading, ensuring a remarkable therapeutic efficacy. Currently, the combination of advanced nanoparticles and novel therapeutic strategies is the most active research area in periodontitis treatment. In this review, we first introduce the pathogenesis of periodontitis, and then summarize the state-of-the-art nanotherapeutic strategies based on the triple concerto of antibacterial activity, immunomodulation and periodontium regeneration, particularly focusing on the therapeutic mechanism and ingenious design of nanomedicines. Finally, the challenges and prospects of nano therapy for periodontitis are discussed from the perspective of current treatment problems and future development trends. Graphical Abstract
Article
Background: Aberrant deoxyribonucleic acid (DNA) contributes to inflammasome orchestrated progression of chronic inflammatory diseases like diabetes and periodontitis. The purpose of the present study was to estimate salivary levels of DNA sensing inflammasomes; absent in melanoma 2 (AIM2), interferon γ inducible protein (IFI16) and cytokine interleukin 18 (IL18) in individuals with periodontitis, diabetes and healthy controls and interpret its association with periodontal and diabetic parameters. Methods: Salivary levels of AIM2, IFI16 and IL18 was estimated by enzyme linked immunosorbent assay (ELISA) in a total of 120 individuals (n = 30 in each group), namely healthy (Group 1), periodontitis (Group 2), diabetes (Group 3) and diabetes with periodontitis (Group 4). Correlations of inflammasome levels and periodontal clinical parameters - plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment level (CAL) and periodontal inflamed surface area (PISA)was performed. Multiple regression was carried out to predict AIM2 and IFI16 with various independent variables. Results: The mean salivary levels of AIM2, IFI16 and IL18 were highest in diabetes with periodontitis (Group 4) and least in healthy (Group 1) and statistically significant between the groups (p = 0.000). Significant positive correlation between clinical periodontal parameters and AIM2, IFI16 and IL8 was present (p≤0.05). Multiple regression showed HbA1C (p = 0.002), GI (p = 0.016), PISA (p = 0.002) and CAL (p = 0.004) were significant predictors of AIM2, while HbA1C (p = 0.012), PISA (P = 0.003) and CAL (p = 0.007) predicted IFI16. Conclusion: The results of the present study showed higher levels of AIM2, IFI16 and IL18 in saliva of individuals with diabetes and periodontitis. HbA1C, PISA and CAL were significant independent predictors of salivary AIM2 and IFI16 levels. This article is protected by copyright. All rights reserved.
Article
IL-33 is a relatively new member of the IL-1 cytokine family, which plays a unique role in autoimmune diseases, particularly some oral diseases dominated by immune factors. The IL-33/ST2 axis is the main pathway by which IL-33 signals affect downstream cells to produce an inflammatory response or tissue repair. As a newly discovered pro-inflammatory cytokine, IL-33 can participate in the pathogenesis of autoimmune oral diseases such as Sjogren's syndrome and Behcet's disease. Moreover, the IL-33/ST2 axis also recruits and activates mast cells in periodontitis, producing inflammatory chemokines and mediating gingival inflammation and alveolar bone destruction. Interestingly, the high expression of IL-33 in the alveolar bone, which exhibits anti-osteoclast effects under appropriate mechanical loading, also confirms its dual role of destruction and repair in an immune-mediated periodontal environment. This study reviewed the biological effects of IL-33 in autoimmune oral diseases, periodontitis and periodontal bone metabolism, and elaborated its potential role and impact as a disease enhancer or a repair factor.
Article
Background: Periodontal diagnosis is based on recording clinical parameters including bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment loss (CAL). These techniques may be prone to errors due to different factors. Available biomarkers in the oral biofluid such as interleukin (IL)-1β could provide solutions for these issues. The study aimed to determine the potential of salivary IL-1β to differentiate periodontal health from disease and between gingivitis and periodontitis. Methods: Patients with gingivitis (N.=25), periodontitis (N.=50), and healthy periodontium (N.=25) were recruited for this study. For each patient, whole unstimulated saliva was collected followed by recording periodontal parameters namely; Plaque Index (PI), BOP, PPD, CAL. Level of salivary IL-1β was assayed by using enzyme-linked immunosorbent assays. Sensitivity and specificity of IL-1β, to differentiate any given condition, was determined by Receiver operating characteristic curve and area under the curve (AUC). Results: Both BOP and PI were significantly higher in association with gingivitis and periodontitis groups as compared to controls. Concentration of salivary IL-1β in periodontal health was significantly lower than gingivitis and periodontitis groups. The biochemical analyses showed that salivary IL-1β differentiated periodontal health from gingivitis (AUC 0.949) and periodontitis (AUC 0.852) but could not discriminate gingivitis from periodontitis (AUC 0.532). The proposed cut-off points to differentiate periodontal health from gingivitis was 103.8 pg/mL, while the value of the biomarker to differentiate periodontal health from periodontitis was 102.0 pg/mL. Conclusions: Salivary IL-1β could be a reliable biomarker with a good level of accuracy to differentiate periodontal health from disease but not to discriminate gingivitis from periodontitis.
Article
Full-text available
Periodontitis is a multi-faceted inflammatory disease that impacts the gingiva and the structures that support our teeth, and may eventually increase tooth mobility and the risk of tooth loss. Inflammation is a viable therapeutic target of periodontitis for both biologic (dietary) and host modulatory agents/drugs. Conventional therapeutic approaches for periodontitis, including nonsurgical or surgical periodontal therapy as well as occasional adjunctive antimicrobial therapy, have been only marginally effective. Malnutrition, or at least poor dietary habits, can be highly prevalent among patients with periodontal diseases. As several food nutrients can aid in periodontal healing and regeneration, there is a critical need to evaluate natural dietary sources and supplement ingredients that can counterbalance the inflammatory processes and improve the periodontal status of our patients. Here, we reviewed the current state of knowledge (search period: 2010 to 2022; PubMed and Web of Science) on the anti-inflammatory actions of food ingredients and supplements in clinical studies of patients with periodontal diseases. A diet that includes fruits and vegetables, omega-3 polyunsaturated fatty acids, and supplements of vitamins and plant-derived compounds seems to counteract gingival inflammation and has a promising therapeutic impact in patients with periodontal diseases. Despite the positive indications that several nutrients can be used as an adjunct to periodontal therapy, additional studies with bigger sample sizes and longer follow-up periods are needed to elucidate their therapeutic benefits and the most effective doses and administration.
Article
Activation of inflammation is a type of innate, non-specific defence of the body against harmful factors of external or internal origin. During this process, various types of cytokines are released, including interleukin-1 (IL-1) and interleukin-6 (IL-6), responsible for the intensification of inflammatory reactions and the activation of hepatic acute phase proteins synthesis. IL-1 exists in two isoforms (IL-1α and IL-1β), showing similar, pro-inflammatory biological properties, but differing in origin, place of release and method of activation. The use of IL-1 in the diagnosis of the inflammatory process is limited, mainly due to the short half-life of this cytokine. IL-6 has a pleiotropic nature of action by using different types of receptors signaling. IL-6 is responsible for activating the synthesis of a wide range of acute phase proteins, also is involved in hematopoiesis and the immune response. IL-6 is a good biomarker of the early phase of inflammation because it has a longer half-life than other cytokines, and its concentration in the blood may increase several thousand times during the first hours after the initiation of inflammation. Due to its high sensitivity in detecting inflammation, C-reactive protein is the most commonly determined highly positive acute phase protein. During the inflammatory process, the pentameric CRP isoform (pCRP) dissociates into monomeric CRP (mCRP), which changes the anti-inflammatory properties of CRP into highly pro-inflammatory. The currently used laboratory tests detect only the pCRP isoform, because it is well soluble in blood and accumulates in it when conversion to mCRP is no longer effective.
Article
Objective We aimed to assess the role of interleukin -1 receptor antagonist (IL-1RA) in a ligature-induced periodontal (LIP) model and the mechanism of IL-1RA in regulating the IL-17-mediated periodontal bone loss. Design Periodontal bone loss was induced through the LIP model in WT and Il1ra -/- mice and measured by micro(μ) CT. Transcription of upstream IL-17 production signals and downstream targets in the ligated gingiva was compared by the real-time-quantitative PCR (RT-PCR) between WT and Il1ra-/- mice. Single-cell suspensions were prepared in gingiva and cervical lymph nodes and were analyzed by fluorescence-activated cell sorting to quantify IL-17⁺ cells and IL-17-secreting subpopulation. We locally delivered neutralizing IL-17 antibody in the ligated gingiva and compared the bone loss with the isotype control antibody-treated Il1ra-/- mice. Results Il1ra -/- mice manifested significant bone loss as compared to WT mice in the LIP model. Il17 and IL-17-associated transcripts (Il1b, Il6, Il23, Tgfb), Inos, Mrc1, Mmp13, and Rank were upregulated in the gingiva of Il1ra -/- mice in comparison to WT mice. Significantly more IL-17⁺ immune cells (CD45⁺IL17⁺) are present in the gingiva of Il1ra-/- mice with the majority of being TCR γδ T cells (CD45⁺IL⁻17⁺CD3⁺TCR γδ⁺) than WT mice. The anti-IL-17 neutralizing antibody treatment attenuated the alveolar bone loss in the LIP model. Conclusion IL-1RA plays a protective role in the murine LIP model by suppressing IL-17 expansion and preventing a hyper-IL-17 response in the gingiva.
Article
Chronic inflammation caused by immune cells and their mediators is a characteristic of atherosclerosis. Interleukin-38 (IL-38), a member of the IL-1 family, exerts multiple anti-inflammatory effects via specific ligand-receptor interactions. Upon recognizing a specific receptor, IL-38 restrains mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NK-κB), or other inflammation-related signaling pathways in inflammatory disease. Further research has shown that IL-38 also displays anti-atherosclerotic effects and reduces the occurrence and risk of cardiovascular events. On the one hand, IL-38 can regulate innate and adaptive immunity to inhibit inflammation, reduce pathological neovascularization, and inhibit apoptosis. On the other hand, it can curb obesity, reduce hyperlipidemia, and restrain insulin resistance to reduce cardiovascular disease risk. Therefore, this article expounds on the vital function of IL-38 in the development of atherosclerosis to provide a theoretical basis for further in-depth studies of IL-38 and insights on the prophylaxis and treatment of atherosclerosis.
Article
Objective This study investigated the main mechanism and role of caspase-11/4 as a pattern recognition receptor (PRR) in periodontitis through caspase-11 inhibition. Design Clinical tissue samples were collected from patients with periodontitis and healthy volunteers and evaluated through hematoxylin–eosin (HE) staining, immunohistochemical (IHC) staining, and real-time quantitative PCR (RT-qPCR). In the rat periodontitis model, both these staining procedures, RT-qPCR, and western blotting were used to evaluate the histological, mRNA, and protein levels of caspase-11, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). In vitro, the role of caspase-11, inhibited by siRNA, was investigated by analyzing the mRNA and protein levels of IL-1β and TNF-α in Porphylinomonas gingivalis (P. gingivalis) lipopolysaccharide (LPS)-stimulated Raw264.7 macrophages. Results Histological and molecular biological results of clinical and experimental animal periodontitis samples indicated that caspase-11/4 mRNA and protein levels significantly increased in inflammatory tissues. Caspase-11 is mainly distributed in leukocytes, which are labeled by CD45 in the submucosa. In vitro results further confirmed that the expression of caspase-11/4, IL-1β, and TNF-α significantly increased in LPS-stimulated macrophages, and these changes were significantly attenuated by inhibiting caspase-11/4 expression. Conclusions The function of caspase-11 in rat periodontitis models is similar to that of caspase-4 in human clinical periodontitis. IL-1β and TNF-α release in periodontitis depends on the recognition of P. gingivalis LPS by caspase-11/4.
Article
Aim: CCR2 plays important roles in many inflammatory and bone metabolic diseases, but its specific role in periodontitis is unknown. In the present study, we aimed to explore the role of CCR2 in the progression of periodontitis and evaluate the effect of cenicriviroc (CVC) on periodontitis. Methods: The expression of CCR2 was studied in patients with periodontitis and in ligation-induced murine model of periodontitis. The role of CCR2 in promoting inflammation and bone resorption in periodontitis was evaluated in Ccr2-/- mice and wild-type mice. The effect of CVC in the prevention and treatment of periodontitis was evaluated by systemic and local medication. Micro-CT, Hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, real-time qPCR, ELISA, and flow cytometric were used for histomorphology, molecular biology and cytology analysis respectively. Results: In this study, we demonstrated that CCR2 was highly expressed in human and murine periodontitis and that CCR2 deficiency was associated with decreased inflammation, alveolar bone resorption, osteoclast number, monocyte and macrophage infiltration. Prevention and treatment with CVC significantly reduced the severity of periodontitis, regardless of whether it was administered systemically or locally. Conclusion: CCR2 plays an important role in the development and progression of periodontitis and CVC is a potential drug for the prevention and treatment of periodontitis.
Article
Full-text available
Objective Interleukin (IL)-17A and IL-18 have been proposed to play important roles in periodontitis and type 2 diabetes mellitus (DM), but human data are conflicting. The present study aimed to investigate the roles of IL-17A and IL-18 in periodontitis and DM by measuring salivary and serum levels, respectively. Materials and methods A total of 49 participants with type 2 DM and 25 control subjects without type 2 DM were recruited. A periodontal screening and recording (PSR) index (0, 1–2, 3, and 4) was used to classify whether these subjects had periodontitis. Salivary and serum IL-17A and IL-18 levels were measured by enzyme-linked immunosorbent assay. Multiple linear regression analyses were used to evaluate the associations between these cytokines and clinical parameters. Results Salivary IL-17A levels were not significantly different between patients with DM and controls, however, the levels were significantly higher in controls with periodontitis than those without periodontitis (p = 0.031). Salivary IL-17A levels were significantly associated with the PSR index (β = 0.369, p = 0.011). Multiple linear regression analyses revealed the association of salivary IL-18 levels and fasting plasma glucose (β = 0.270, p = 0.022) whereas serum IL-18 levels were associated with HbA1C (β = 0.293, p = 0.017). No correlation between salivary and serum levels of IL-17A and IL-18 was found. Conclusion Salivary IL-17A was strongly associated with periodontitis, whereas salivary IL-18 was associated with FPG and serum IL-18 was associated with HbA1C. These results suggest the role of these cytokines in periodontal inflammation and DM.
Article
Full-text available
The most important development in the epidemiology of periodontitis in the USA during the last decade is the result of improvements in survey methodologies and statistical modeling of periodontitis in adults. Most of these advancements have occurred as the direct outcome of work by the joint initiative known as the Periodontal Disease Surveillance Project by the Centers for Disease Control and Prevention and the American Academy of Periodontology that was established in 2006. This report summarizes some of the key findings of this important initiative and its impact on our knowledge of the epidemiology of periodontitis in US adults. This initiative first suggested new periodontitis case definitions for surveillance in 2007 and revised them slightly in 2012. This classification is now regarded as the global standard for periodontitis surveillance and is used worldwide. First, application of such a standard in reporting finally enables results from different researchers in different countries to be meaningfully compared. Second, this initiative tackled the concern that prior national surveys, which used partial‐mouth periodontal examination protocols, grossly underestimated the prevalence of periodontitis of potentially more than 50%. Consequently, because previous national surveys significantly underestimated the true prevalence of periodontitis, it is not possible to extrapolate any trend in periodontitis prevalence in the USA over time. Any difference calculated may not represent any actual change in periodontitis prevalence, but rather is a consequence of using different periodontal examination protocols. Finally, the initiative addressed the gap in the need for state and local data on periodontitis prevalence. Through the direct efforts of the Centers for Disease Control and Prevention and the American Academy of Periodontology initiative, full‐mouth periodontal probing at six sites around all nonthird molar teeth was included in the 6 years of National Health and Nutrition Examination Surveys from 2009‐2014, yielding complete data for 10 683 dentate community‐dwelling US adults aged 30 to 79 years. Applying the 2012 periodontitis case definitions to the 2009‐2014 National Health and Nutrition Examination Surveys data, the periodontitis prevalence turned out to be much greater than previously estimated, namely affecting 42.2% of the population with 7.8% of people experiencing severe periodontitis. It was also discovered that only the moderate type of periodontitis is driving the increase in periodontitis prevalence with age, not the mild or the severe types whose prevalence do not increase consistently with age, but remain ~ 10%‐15% in all age groups of 40 years and older. The greatest risk for having periodontitis of any type was seen in older people, in males, in minority race/ethnic groups, in poorer and less educated groups, and especially in cigarette smokers. The Centers for Disease Control and Prevention and the American Academy of Periodontology initiative reported, for the first time, the periodontitis prevalence estimated at both local and state levels, in addition to the national level. Also, this initiative developed and validated in field studies a set of eight items for self‐reported periodontitis for use in direct survey estimates of periodontitis prevalence in existing state‐based surveys. These items were also included in the 2009‐2014 National Health and Nutrition Examination Surveys for validation against clinically determined cases of periodontitis. Another novel result of this initiative is that, for the first time, the geographic distribution of practicing periodontists in relation to the geographic distribution of people with severe periodontitis is illustrated. In summary, the precise periodontitis prevalence and distribution among subgroups in the dentate US noninstitutionalized population aged 30‐79 years is better understood because of application of valid periodontitis case definitions to full‐mouth periodontal examination, in combination with reliable information on demographic and health‐related measures. We now can monitor the trend of periodontitis prevalence over time as well as guide public health preventive and intervention initiatives for the betterment of the health of the adult US population.
Article
Full-text available
Periodontitis is a prevalent chronic inflammatory disease due to the host response (IL-1β, IL-6, TNF-α and IL-17A) to oral bacteria such as Porphyromonas gingivalis. The newer members of the IL-1 family, IL-36s (IL-36α/IL-36β/IL-36γ/IL-36Ra/IL-38) are known to be involved in host defense against P. gingivalis in oral epithelial cells (OECs) and are considered as key inflammatory mediators in chronic diseases. The aim of this study was to investigate the potential role of IL-36s in periodontitis. We showed here that IL-36γ mRNA gingival expression is higher in periodontitis patients, whereas IL-36β and IL-36Ra mRNA expression are lower compared to healthy controls. Interestingly, the elevated IL-36γ expression in patients is positively correlated with the RANKL/OPG ratio, an index of bone resorption. In vitro, IL-36γ expression was induced through TLR2 activation in primary OECs infected with P. gingivalis but not in gingival fibroblasts, the most widespread cell type in gingival connective tissue. In OECs, recombinant IL-36γ enhanced the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α and IL-36γ), of TLR2 and importantly, the RANKL/OPG ratio. These findings suggest that IL-36γ could be a pivotal inflammatory player in periodontitis by perpetuating gingival inflammation and its associated alveolar bone resorption and could be a relevant therapeutic target.
Article
Full-text available
Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of NLRP3 inflammasome is mediated by highly diverse stimuli. Upon activation, NLRP3 protein recruits the adapter ASC protein, which recruits the procaspase-1 resulting in its cleavage and activation, inducing the maturation, and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is implicated in various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative diseases; raising a tremendous clinical interest in exploring the potential inhibitors of NLRP3 inflammasome. Recent investigations have disclosed various inhibitors of the NLRP3 inflammasome pathway which were validated through in vitro studies and in vivo experiments in animal models of NLRP3-associated disorders. Some of these inhibitors directly target the NLRP3 protein whereas some are aimed at other components and products of the inflammasome. Direct targeting of NLRP3 protein can be a better choice because it can prevent off target immunosuppressive effects, thus restrain tissue destruction. This paper will review the various pharmacological inhibitors of the NLRP3 inflammasome and will also discuss their mechanism of action.
Article
Full-text available
Background: The inflammasome modulates the release of key pro-inflammatory cytokines associated with periodontal disease pathogenesis. The aim of this study was to evaluate the expression of proteins that regulate the inflammasome, namely Pyrin domain-only proteins (POPs), Caspase recruitment domain (CARD)-only proteins (COPs), and tripartite motif-containing (TRIM) proteins, in periodontal diseases. Methods: A total of 68 participants (34 males and 34 females) were divided into 4 groups, including periodontal health (H), gingivitis (G), chronic periodontitis (CP) and aggressive periodontitis (AgP) based on clinical parameters. Gingival tissue samples were obtained from all participants for reverse transcription polymerase chain reaction (RT-PCR)-based gene expression analyses of molecules that regulate the inflammasome, including Apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, Interleukin-1β (IL-1β), Interleukin-18 (IL-18), Nucleotide-binding domain, leucine rich family (NLR) Pyrin Domain Containing 3 (NLRP3), NLR family Pyrin Domain Containing 2 (NLRP2), (Absent in Melanoma 2) AIM2, POP1, POP2, CARD16, CARD18, TRIM16 and TRIM20 by (RT-PCR). Results: NLRP3 and IL-1β were upregulated in the G, CP and AgP groups compared with group H (p<0.05). AIM2 was downregulated in the CP group compared with the H, G, and AgP groups (p<0.05). TRIM20, TRIM16 and CARD18 were downregulated in the G, CP and AgP groups compared with the H group (p<0.05). POP1 and POP2 were downregulated in the CP and AgP, and AgP and G groups, respectively (p<0.05). Conclusion: Active periodontal disease may result in downregulation of inflammasome regulators that may increase the activity of NLRP3 and IL-1β in periodontal disease. This article is protected by copyright. All rights reserved.
Article
Full-text available
Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.
Article
Full-text available
Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.
Article
Full-text available
Periodontitis is characterized by the progressive destruction of tooth-supporting alveolar bone, which is mainly caused by chronic inflammation in response to persistent bacterial insult. It has recently become clear that the pathogenesis of periodontitis is associated with a high ratio of proinflammatory M1 (classically activated) macrophages to anti-inflammatory M2 (alternatively activated). To decrease the inflammatory activity, we locally delivered the C-C motif chemokine ligand 2 (CCL2) using controlled-release microparticles (MPs). CCL2 is known to promote chemotaxis of M0 or M2 phenotype macrophages to the inflamed site and induce M2 phenotype polarization locally. Our in vitro data showed that CCL2 increased the number of M2 phenotype macrophages, decreased TNF-α secretion, and enhanced chemotaxis of RAW264.7 cells toward CCL2 MPs. Moreover, we induced periodontal disease in 2 animal models through inoculation of Porphyromonas gingivalis and ligature around the murine molar. Micro-computed tomography analysis showed significant reduction of alveolar bone loss in the CCL2 MP treatment group when compared with a blank MP group and a no-treatment periodontitis group in both models. Immunohistologic analysis showed a significant increase in the M2 phenotype subset and a decrease in the M1 phenotype subset in the CCL2 MP group of the P. gingivalis-induced model. Also, in both models, tartrate-resistant acidic phosphatase staining showed significantly fewer numbers of osteoclasts in the CCL2 MP group in alveolar bone area. Moreover, quantitative polymerase chain reaction results showed a significant increase in IL-1RA (interleukin 1 receptor antagonist) mRNA expression and a decrease in RANKL (receptor activator of nuclear factor kappa-Β ligand) mRNA expression in the CCL2 MP group in the ligature model. In summary, manipulation of endogenous M2 phenotype macrophages with CCL2 MPs decreased the M1 phenotype:M2 phenotype ratio and prevented alveolar bone loss in mouse periodontitis models. The delivery of CCL2 MPs provides a novel approach to treat periodontal disease.
Article
Full-text available
IL-36 cytokines, a subgroup of IL-1 family, comprise IL-36α, IL-36β, and IL-36γ agonists, abundantly expressed in psoriatic skin, and IL-36RA and IL-38 antagonists. In psoriatic skin, IL-36 cytokines interfere with keratinocyte cornification programs and induce the release of antimicrobial peptides and chemokines active on neutrophils and Th17 lymphocytes. To date, the role of IL-38 antagonist in psoriasis remains to be defined. Here, we demonstrate that skin and circulating IL-38 levels are reduced in psoriatic patients and in other skin diseases characterized by neutrophilic infiltrate. In psoriasis, the balance of IL-36γ agonist/IL-38 antagonist serum levels is in favor of agonists and is closely associated with disease severity. Interestingly, IL-38 is upregulated by anti-IL-17A biological treatment and positively correlates with the therapeutic efficacy of secukinumab in psoriatic patients. The downregulation of IL-38 expression is strictly related to keratinocyte de-differentiation triggered by the inflammatory cytokines IL-36γ, IL-17, and IL-22. Finally, we demonstrate that administration of recombinant full-length IL-38 counteracts in vitro the biological processes induced by IL-36γ in human keratinocytes and endothelial cells and attenuates in vivo the severity of the psoriasiform phenotype induced by IMQ in mice. Such effects are achieved by restoring the physiological programs of keratinocyte proliferation and differentiation, and reducing the immune cell infiltrates.
Article
Full-text available
There is no agnostic GWAS evidence for the genetic control of IL-1β expression in periodontal disease. Here we report a GWAS for "high" gingival crevicular fluid IL-1β expression among 4910 European-American adults and identify association signals in the IL37 locus. rs3811046 at this locus (p = 3.3 × 10 −22) is associated with severe chronic periodontitis (OR = 1.50; 95% CI = 1.12-2.00), 10-year incident tooth loss (≥3 teeth: RR = 1.33; 95% CI = 1.09-1.62) and aggressive periodontitis (OR = 1.12; 95% CI = 1.01-1.26) in an independent sample of 4927 German/Dutch adults. The minor allele at rs3811046 is associated with increased expression of IL-1β in periodontal tissue. In RAW macrophages, PBMCs and transgenic mice, the IL37 variant increases expression of IL-1β and IL-6, inducing more severe periodontal disease, while IL-37 protein production is impaired and shows reduced cleavage by caspase-1. A second variant in the IL37 locus (rs2708943, p = 4.2 × 10 −7) associates with attenuated IL37 mRNA expression. Overall, we demonstrate that IL37 variants modulate the inflamma-tory cascade in periodontal disease.
Article
Full-text available
Objectives: The immune system has an important role in the development of systemic lupus erythematosus (SLE) and chronic periodontitis (CP). Altered cytokines levels characterise both diseases and contributes to periodontal tissue damage in CP and to macrocomplexes deposition with connective tissue destruction in SLE. This study aimed to evaluate the production of salivary cytokines in patients with SLE and its association with periodontal status. Methods: The sample comprised 70 SLE patients and 70 paired controls. SLE activity and damage were scored using Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Subjects were classified as without or with CP. Salivary concentrations of IL-33, MMP2/TIMP2, RANK and OPG were measured by ELISA, while IL-2, IFNγ, TNFα, IL-4, IL-6, IL-10 and IL-17A were determined by Cytometric Bead Array. Linear regression models analysed association among SLE, CP and salivary cytokines. Results: IL-6 and IL-17A concentrations were significantly higher in SLE/CP patients than controls/CP. Concentrations of IL-6, IL-17A and IL-33 were increased in SLE/CP individuals when compared to SLE without CP. Multivariate model revealed association of cumulative dose of corticoids with periodontal damage and of IL-33 salivary concentration with SLE activity. Conclusions: Our findings suggest that long-term therapy with corticoids would contribute with periodontal destruction in SLE patients. Moreover, the increased levels of IL-6, IL-17A and IL-33 in saliva of SLE subjects with CP may signal it as possible inflammatory pathways in this process.
Article
Full-text available
IL-36 cytokines are important regulators of mucosal homeostasis and inflammation. We have previously established that oral epithelial cells upregulate IL-36γ expression in response to the bacterial pathogen Porphyromonas gingivalis . Here, we have established that IL-36γ can stimulate the gene expression of mechanistically-distinct antimicrobial proteins, including the peptidoglycan amidase PGLYRP2, in oral epithelial cells (e.g. TIGK cells). PGLYRP2 gene expression was not stimulated by either IL-17 or IL-22, and thus demonstrating selectivity in the regulation of PGLYRP2 by IL-36γ. The IL-36γ-inducible expression of PGLYRP2 was shown to be mediated by IRAK1- and p38 MAP kinase-dependent signaling. Furthermore, our finding that IL-36γ-inducible PGLYRP2 expression was reduced in proliferating TIGK cells but increased in terminally differentiating cells suggests that control of PGLYRP2 expression is associated with the maturation of the oral epithelium. PGLYRP2 expression in TIGK cells can also be directly stimulated by oral bacteria. However, the extracellular gingipain proteases (Kgp and RgpA/B) produced by P. gingivalis , which are critical virulence factors, can antagonize PGLYRP2 expression. Thus, the expression of IL-36γ by oral epithelial cells in response to P. gingivalis might enable the subsequent autocrine stimulation of PGLYRP2 expression. In summary, our data identify how IL-36γ may promote oral mucosal homeostasis by regulating PGLYRP2 expression.
Article
Full-text available
Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. Candida albicans is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to C. albicans are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate Type-17 immune responses to clear C. albicans infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. In this study, we identify IL-36 cytokines as a new player in these responses. We show that C. albicans infection of the oral mucosa induces the production of IL-36. As with IL-1α/β, induction of epithelial IL-36 depends on the hypha-associated peptide toxin Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-κB, and PI3K signaling and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R-/- mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17-dependent genes, indicating that this protection occurs via an alternative pathway to IL-1-driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell-driven protective pathways in immunity to oral C. albicans infection.
Article
Full-text available
Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8⁺ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
Article
Full-text available
IL-37 is a unique member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non-immune cells produce IL-37 precursor following pro-inflammatory stimuli. Following activating cleavage by caspase-1, mature IL-37 translocates to the nucleus, where it suppresses transcription of pro-inflammatory genes. Both precursor and mature IL-37 are also secreted in the extracellular space, where they bind IL-18Rα and recruit the IL-1R8 (formerly TIR8 or SIGIRR), which transduces anti-inflammatory signals by suppressing NF-kB and MAPK and by activating Mer-PTEN-DOK pathways. During inflammation, IL-37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL-37 and wild type mice treated with recombinant human IL-37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation-induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL-37 likely functions to limit excessive inflammation: accordingly, IL-37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL-37, and discuss the potential for development of this cytokine as a therapeutic agent.
Article
Full-text available
IL-38 belongs to the IL-36 cytokines, which in turn are part of the IL-1 family. The first biological function of IL-38 described was blocking the activation of the IL-36R signaling similar to IL-36Ra. Since IL-36 cytokines require processing in order to become fully active, it is likely that IL-38 also must be processed to become maximally active. However, the protease(s) responsible for this is currently not known. In addition of IL-38 binding IL-36R, it has been proposed it can also interact with the co-receptor TIGIRR2. IL-38 is expressed in several tissues including tonsils, placenta, heart and brain, and IL-38 has been implicated in a wide variety of diseases including cardiovascular and autoimmune disease. Here, we discuss the discovery and biological function of IL-38, and its role in the pathogenesis of a wide variety of diseases.
Article
Full-text available
Dendritic cells (DCs) are antigen-presenting cells that capture, process and present antigens to lymphocytes to initiate and regulate the adaptive immune response. DCs detect bacteria in skin and mucosa and migrate into regional lymph nodes, where they stimulate antigen-specific T and B lymphocyte activation and proliferation. DCs direct CD4 T cells to differentiate to T cell subsets such as Th1, Th2, Th17 and Treg cells. The periodontium is chronically exposed to oral bacteria that stimulate an inflammatory response to induce gingivitis or periodontitis. DCs play both a protective and destructive role through activation of the acquired immune response and are also reported to be a source of osteoclast precursors that promote bone resorption. FOXO1, a member of the forkhead box O family of transcription factors, plays a significant role in the activation of DCs. The function of DCs in periodontal inflammation has been investigated in a mouse model by lineage specific deletion of FOXO1 in these cells. Deletion of FOXO1 reduces DC protective function and enhances susceptibility to periodontitis. The kinase Akt, phosphorylates FOXO1 to inhibit FOXO activity. Thus the Akt-FOXO1 axis may play a key role in regulating DCs to have a significant impact on periodontal disease. This article is protected by copyright. All rights reserved.
Article
Full-text available
Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation. Chronic periodontitis predominantly affects adults, but aggressive periodontitis may occasionally occur in children. Periodontal disease initiation and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defences of the host, leading to inflammation and disease. This pathophysiological situation persists through bouts of activity and quiescence, until the affected tooth is extracted or the microbial biofilm is therapeutically removed and the inflammation subsides. The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility). Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi-Annual basis. New treatment modalities that are actively explored include antimicrobial therapy, host modulation therapy, laser therapy and tissue engineering for tissue repair and regeneration.
Article
Full-text available
Significance Inflammatory responses are often characterized by elevated levels of cytokines, but the complex interplay among peptides and cytokines is not often considered. Here, we report that the cytokine IL-33, administered in combination with the proinflammatory peptide substance P (SP), causes a marked increase in tumor necrosis factor synthesis and secretion from cultured human mast cells. These responses are mediated via the activation of the SP receptor NK-1 and the IL-33 receptor ST2 and can be inhibited by the natural flavonoid methoxyluteolin. Our findings reveal interactions that increase the understanding of inflammation and offer new directions for the development of antiinflammatory drugs.
Article
Full-text available
Background Periodontitis results from the interaction between a subgingival biofilm and host immune response. Changes in biofilm composition are thought to disrupt homeostasis between the host and subgingival bacteria resulting in periodontal damage. Chronic systemic inflammatory disorders have been shown to affect the subgingival microbiota and clinical periodontal status. However, this relationship has not been examined in subjects with systemic lupus erythematosus (SLE). The objective of our study was to investigate the influence of SLE on the subgingival microbiota and its connection with periodontal disease and SLE activity. Methods We evaluated 52 patients with SLE compared to 52 subjects without SLE (control group). Subjects were classified as without periodontitis and with periodontitis. Oral microbiota composition was assessed by amplifying the V4 region of 16S rRNA gene from subgingival dental plaque DNA extracts. These amplicons were examined by Illumina MiSeq sequencing. ResultsSLE patients exhibited higher prevalence of periodontitis which occurred at a younger age compared to subjects of the control group. More severe forms of periodontitis were found in SLE subjects that had higher bacterial loads and decreased microbial diversity. Bacterial species frequently detected in periodontal disease were observed in higher proportions in SLE patients, even in periodontal healthy sites such as Fretibacterium, Prevotella nigrescens, and Selenomonas. Changes in the oral microbiota were linked to increased local inflammation, as demonstrated by higher concentrations of IL-6, IL-17, and IL-33 in SLE patients with periodontitis. ConclusionsSLE is associated with differences in the composition of the microbiota, independently of periodontal status.
Article
Full-text available
Introduction Chronic Periodontitis (CP) is an inflammatory disease of bacterial origin that results in alveolar bone destruction. Porphyromonas gingivalis (Pg), one of the main periopathogens, initiates an inflammatory cascade by host immune cells thereby increasing recruitment and activity of osteoclasts, the bone resorbing cells, through enhanced production of the crucial osteoclastogenic factor, RANK-L. Antibodies directed against some cytokines (IL-1β, IL-6 and TNF-α) failed to exhibit convincing therapeutic effect in CP. It has been suggested that IL-33, could be of interest in CP. Objective the present study aims to analyze whether and how IL-33 and RANK-L and/or their interplay are involved in the bone destruction associated to CP. Material and Methods mRNAs and protein expressions of IL-33 and RANK-L were analyzed in healthy and CP human gingival samples by immunohistochemistry (IHC) and RT-qPCR. Murine experimental periodontitis (EP) was induced using Pg infected ligature and Pg free ligature around the first maxillary molar. Alveolar bone loss was recorded by μCT. Mouse gingival explants were stimulated for 24 hours with IL-33 and RANK-L mRNA expression investigated by RT-qPCR. Human oral epithelial cells were infected by Pg for 6, 12; 24 hours and IL-33 and RANK-L mRNA expressions were analyzed by RT-qPCR. Results IL-33 is overexpressed in gingival epithelial cells in human affected by CP as in the murine EP. In human as in murine gingival cells, RANK-L was independently induced by Pg and IL-33. We also showed that the Pg-dependent RANK-L expression in gingival epithelial cells occured earlier than that of IL-33. Conclusion Our results evidence that IL-33 overexpression in gingival epithelial cells is associated with CP and may trigger RANK-L expression in addition to a direct effect of Pg. Finally, IL-33 may act as an extracellular alarmin (danger signal) showing proinflammatory properties in CP perpetuating bone resorption induced by Pg infection.
Article
Full-text available
Interleukin 37 (IL-37) has been reported to play a significant role in innate immune response and to be involved in several kinds of cancers. However, the investigation of association between IL-37 and oral mucosa carcinogenesis hasn't been clearly established. The aim of the study was to assess IL-37 expression and explore its role in oral mucosa carcinogenesis. The expression of IL-37 increased from normal control (NC) to Oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). Moreover, statistically highly significant difference was present between scores of OLK with and without mild/moderate dysplasia (P < 0.001). In addition, IL-37 expression was lower in OSCC with lymph node metastasis than those without metastasis (P < 0.01). What’s more, overexpression of IL-37 in RAW264.7 cells remarkably reduced the pseudopodia, vacuolization and the expression of IL-6, TNF-α, and IL-1β. Finally, we found IL-37 and its receptor IL-18Rα but not its binding partner IL-18BP have similar tissue location and expression trend in different stages of oral mucosa carcinogenesis. Overall, IL-37 can be used as a biomarker for early oral tumorigenesis and for malignant transformation risk assessment of premalignant lesions.
Article
Full-text available
Objectives This study aimed to examine the IL-1β, IL-1ra, and IL-10 cytokine levels in gingival crevicular fluid (GCF) and serum of familial Mediterranean fever (FMF) and chronic periodontitis (CP) patients, and their response to nonsurgical periodontal therapy. Materials and methods A total of 50 patients, 15 FMF patients with generalized chronic periodontitis (FMF-CP), 15 systemically healthy patients with generalized chronic periodontitis (CP), ten systemically and periodontal healthy controls (HC), and ten periodontally healthy FMF patients (FMF-HC) were enrolled in the study. The cytokine levels in GCF and serum were determined by ELISA. Probing depth, clinical attachment level, and gingival and plaque indices in each participant were also measured. The GCF and clinical parameters at baseline and 6 weeks were recorded. Results The study indicated statistically significant healing of the clinical parameters in both FMF-CP and CP groups after periodontal treatment. GCF IL-1β levels at 6 weeks in FMF-CP group were significantly lower than the CP group (p < 0.05), and GCF IL-1ra levels were significantly decreased at 6 week in the FMF-CP group (p < 0.05). GCF IL-10 levels were significantly higher in the FMF-CP group than in the other groups at baseline and 6 weeks (p < 0.05). There were no significant differences in serum-IL-1β, IL-1ra, and IL-10 levels either FMF-CP or CP groups at baseline or 6 weeks (p > 0.05). Conclusions The results of our study suggested that there was a positive correlation between gingival inflammation and serum cytokine levels in FMF patients and also colchicine treatment showed protective effects on GCF cytokine levels in FMF-CP group. Clinical relevance Following treatment, GCF IL-1β and GCF IL-1ra levels were decreased in FMF-CP group. GCF IL-10 levels were increased in FMF-CP group compared to other groups. Also, the serum cytokine levels associated with periodontal inflammation in FMF patients.
Article
Full-text available
Recent evidence has strongly implicated the IL-1 family cytokines IL-36α, IL-36β, and IL-36γ as key initiators of skin inflammation. Similar to the other members of the IL-1 family, IL-36 cytokines are expressed as inactive precursors and require proteolytic processing for activation; however, the responsible proteases are unknown. Here, we show that IL-36α, IL-36β, and IL-36γ are activated differentially by the neutrophil granule-derived proteases cathepsin G, elastase, and proteinase-3, increasing their biological activity ∼500-fold. Active IL-36 promoted a strong pro-inflammatory signature in primary keratinocytes and was sufficient to perturb skin differentiation in a reconstituted 3D human skin model, producing features resembling psoriasis. Furthermore, skin eluates from psoriasis patients displayed significantly elevated cathepsin G-like activity that was sufficient to activate IL-36β. These data identify neutrophil granule proteases as potent IL-36-activating enzymes, adding to our understanding of how neutrophils escalate inflammatory reactions. Inhibition of neutrophil-derived proteases may therefore have therapeutic benefits in psoriasis.
Article
Significance These findings indicate the important role of IL-38 in the inihibition of neurotensin-stimulated activation of microglia and the resulting release of proinflammatory molecules. Moreover, the reduced expression of IL-38 in the amygdala indicates that it may not be sufficient to prevent inflammation, and that its administration could serve as a novel treatment for children with autism spectrum disorder.
Article
COVID-19 is now recognized as a pandemic throughout the world, leading to a scramble in order to gather knowledge as well as evidence regarding the ‘novel’ corona virus which causes this disease. Chemokines are a family of cytokines which are chemotactic in nature and cause the recruitment of cells of inflammation. Periodontitis has long been attributed to having its pathophysiology rooted in a cytokine response. The recent COVID-19 p