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IL-33 at the Crossroads of Metabolic Disorders and Immunity


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As a cytokine in interleukin-1(IL-1) family, interleukin-33(IL-33) usually exists in the cytoplasm and cell nucleus. When the cells are activated or damaged, IL-33 can be secreted into extracellular and regulate the functions of various immune cells through binding to its specific receptor suppression of tumorigenicity 2 (ST2). Except regulating the function of immune cells including T cells, B cells, dendritic cells (DCs), macrophages, mast cells, and innate lymphoid cells, IL-33 also plays an important role in metabolic diseases and has received an increasing attention. This review summarizes the regulation of IL-33 on different immune cells in lipid metabolism, which will help to understand the pathology of abnormal lipid metabolic diseases, such as atherosclerosis and type 2 diabetes.
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published: 30 January 2019
doi: 10.3389/fendo.2019.00026
Frontiers in Endocrinology | 1January 2019 | Volume 10 | Article 26
Edited by:
Jixin Zhong,
Case Western Reserve University,
United States
Reviewed by:
Yanbo Yu,
Qilu Hospital of Shandong University,
Takashi Yazawa,
Asahikawa Medical University, Japan
Fenna Sille,
Johns Hopkins University,
United States
Lijing Yang
Specialty section:
This article was submitted to
Experimental Endocrinology,
a section of the journal
Frontiers in Endocrinology
Received: 23 October 2018
Accepted: 15 January 2019
Published: 30 January 2019
Tu L and Yang L (2019) IL-33 at the
Crossroads of Metabolic Disorders
and Immunity.
Front. Endocrinol. 10:26.
doi: 10.3389/fendo.2019.00026
IL-33 at the Crossroads of Metabolic
Disorders and Immunity
Lei Tu 1and Lijing Yang2
1Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,
Wuhan, China, 2Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
As a cytokine in interleukin-1(IL-1) family, interleukin-33(IL-33) usually exists in the
cytoplasm and cell nucleus. When the cells are activated or damaged, IL-33 can be
secreted into extracellular and regulate the functions of various immune cells through
binding to its specific receptor suppression of tumorigenicity 2 (ST2). Except regulating
the function of immune cells including T cells, B cells, dendritic cells (DCs), macrophages,
mast cells, and innate lymphoid cells, IL-33 also plays an important role in metabolic
diseases and has received an increasing attention. This review summarizes the regulation
of IL-33 on different immune cells in lipid metabolism, which will help to understand
the pathology of abnormal lipid metabolic diseases, such as atherosclerosis and type
2 diabetes.
Keywords: IL-33, metabolism, diabetes, innate & adaptive immune response, ST2
IL-33, a new member of the IL-1 family, was discovered in 2005 (1) while its receptor ST2
containing intracellular domain Toll/IL-1R (TIR) was found in BALB/c-3t3 mouse fibroblasts in
1989 (1,2). The receptor complex of IL-33 is composed of ST2 and interleukin-1 receptor accessory
protein (IL-1RAcP). IL-33 mediates its biological effect through binding to its specific receptor ST2
(2,3), whereas the expression of ST2 is restricted and determines the cellular responsiveness to
IL-33 treatment (3).Two forms of ST2 have been demonstrated, a membrane-bound form (ST2L)
and a soluble form (sST2), the latter which prevents its signaling as the decoy receptor for IL-
33. IL-33 is mainly expressed in fibroblasts, epithelial cells and endothelial cells, and especially
in high endothelial venules (HEV) (4). Indeed, as designated as an “alarmin,” IL-33 is usually
released after cell injury to alert the immune system and initiate repair processes. In a recent study,
islet mesenchymal-cell-derived IL-33 has been identified as an islet immunoregulatory feature
(5). As the receptor of IL-33, ST2 is expressed in many immune cells. IL-33 is a dual-function
cytokine. In the absence of inflammatory stimulation, IL-33 is located in the nucleus as a nuclear
factor. Once the cell is damaged and/or necrotic, IL-33 can be released from the nucleus and
then act as an endogenous “alarmin” (4). The activation signal produced by IL-33/ST2 pathway is
transmitted to the cell and a series of signal transmissions activate nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway to
regulate immune response (1,6). Under normal physiological condition, inflammation induced by
a dysregulated lipid metabolism is benefit for the maintenance of homeostasis and is controlled to
avoid excessive damage to the host. However, if not properly controlled, the inflammatory response
will promote the excessive production of lipid metabolites, inflammatory cytokines and adhesion
molecules, which lead to acute or chronic diseases (7), such as obesity, non-alcoholic steatohepatitis
(NASH), atherosclerosis, and acute cardiovascular events. To date, an increasing body of evidence
has demonstrated that IL-33 plays a critical role in the lipid metabolism. This review highlights
Tu and Yang IL-33 Regulates Metabolic Disorders
the function of IL-33/ST2 axis on different immune cells in the
metabolic disorders.
IL-33 and ST2 have been shown to be expressed in human and
murine adipose tissue, and IL-33 expression is strongly correlated
with leptin expression in human adipose tissue (8). In addition,
administration of IL-33 increases browning of white adipose
tissue and energy expenditure in mice (9). These observations
show that a critical role of IL-33 played in the adipose tissues
Macrophages have functional plasticity in adipose tissue
inflammation, which can exhibit pro-inflammatory or anti-
inflammatory function. According to the phenotypes and
secreted cytokines, macrophages can be divided into two
categories named as classical activated macrophages (CAM,
M1 type) and alternatively activated macrophages (AAM, M2
type), respectively. CAM are generated in response to helper T1
cells (Th1 cells)-related cytokines, such as interferon-γ(IFN-γ)
and tumor necrosis factor-α(TNF-α), while AAM polarization
is linked to the helper T2 cells (Th2 cells)-related cytokines
(IL-4 and IL-13) (10). Previous studies showed that AAM
could attenuate adipose tissue inflammation and obesity-induced
insulin resistance (1114). It has been showed that ST2 can
be detected on the cell surface of macrophages. IL-33 can
promote the expression of lipopolysaccharide (LPS) receptor
components such as myeloid differentiation factor 2 (MD2), toll-
like receptor (TLR) 4, soluble cluster of differentiation 14 (CD14)
and myeloid differentiation primary response gene 88 (Myd88),
which result in an enhanced inflammatory cytokine production
(15). However, IL-33 administration improves glucose tolerance,
which is associated with the accumulation of M2 macrophages in
adipose tissue of ob/ob mice that are the mutant mice to construct
the model of Type II diabetes (16). As the result of purine
metabolism disorder, gout is a very common metabolic disease
in human (17,18). Hyperlipidaemia is common in gout patients
including increased low-density lipoprotein (LDL) cholesterol
and decreased high-density lipoprotein (HDL) cholesterol (19).
The serum IL-33 expression is predominantly increased in gout
patients compared to healthy controls and positively correlated
with the expression of HDL, while negatively correlated with
LDL expression (20). It has been reported that the elevated
IL-33 level is considerably reduced in renal impairment when
compared with normal renal function in gout patients (2022).
These data suggest that IL-33 may prevent the kidney injury
through regulating the lipid metabolism, which may be resulted
from the AAM polarization.
Although ST2 can be detected on the cell surface of
macrophages, IL-33/ST2 signaling cannot directly promote AAM
polarization. The involvement of IL-33/ST2 signaling in the
differentiation and activation of AAM is associated with type II
cytokines induction (2325). A previous finding showed that a
population of cells expressing ST2 in adipose was potential to
produce large amounts of Th2 cytokines in response to IL-33
(26). Recent studies have named this population as group 2 innate
lymphoid cells (ILC2s), characterized by expressing ST2 receptor,
and secreting type 2 cytokines such as IL-5 and IL-13 in response
to IL-33 (2730). In addition, soluble ST2 can prevent ILC2s from
IL-33 stimulation (31). Recent observation has shown that ILC2s
activation favors macrophages toward a protective AAM, which
lead to a reduced lipid storage and decrease gene expression
of lipid metabolism and adiposeness (32). Furthermore, it has
showed that IL-13Rα2 may act as a critical checkpoint in the
protective effect of the IL-33/IL-13 axis in obesity (33). In
addition, IL-33 promotes βcell function through islet-resident
ILC2s that elicite retinoic acid (RA)-producing capacities in
macrophages and dendritic cells via the secretion of IL-13 and
colony-stimulating factor 2 (5). These data suggest that IL-33
plays a protective role in the adipose tissue inflammation through
regulating macrophage function, which is closely associated with
the activation of ILC2 to produce type 2 cytokine and IL-4Rα
As a subset of T cells, the regulatory T cells (Tregs) play a critical
role in suppressing autoimmune reactivity and have gained an
increasing attention in the autoimmune diseases (34). It is shown
that an impaired Tregs function is investigated in ST2 gene
knockout mice with streptozotocin-induced diabetes, where the
glycaemia and βcell loss are severe (35). Indeed, the exogenous
IL-33 treatment propagates Tregs expressing the ST2 on the
cellular surface, which suggests that the Tregs expansion induced
by IL-33 administration is likely to be the result of a direct effect
of IL-33 on ST2L+Tregs (36,37). Besides, ST2+DCs stimulated
by IL-33 to secrete IL-2, which promotes the selective expansion
of ST2+Tregs vs. non-Tregs, are required for in vitro and in vivo
Tregs expansion (37,38). In the Th1/Th17-mediated allograft
rejection, IL-33 treatment can prevent allograft rejection through
increasing ST2 positive Tregs in mice (39). In the mouse model
of trinitrobenzene sulfonic acid (TNBS)-induced colitis, dextran
sulfate sodium (DSS)-induced colitis or T cell adoptive transfer
induced colitis, IL-33 can increase the number of Foxp3+Tregs
The Tregs also play a immunosuppressive function in obesity-
associated inflammation (43). Interestingly, studies have also
demonstrated that IL-33 maintain homeostasis in adipose tissue.
A high level of ST2 expression is observed on human adipose
tissue Tregs. Furthermore, IL-33 treatment can induce vigorous
population expansion of Tregs in obese mice, and the changes
of metabolic parameters are significantly correlated with the
increased Tregs (44,45). IL-33 signaling through the IL-33
receptor ST2 and the myeloid differentiation factor MyD88
pathway is essential for the development and maintenance
of Tregs in visceral adipose tissue (44). However, ILC2-
intrinsic IL-33 activation is required for Tregs accumulation
in vivo and is independent of ILC2 type 2 cytokines but
partially dependent on direct co-stimulatory interactions via
the inducible costimulator ligand (ICOSL)/ICOS pathway
Frontiers in Endocrinology | 2January 2019 | Volume 10 | Article 26
Tu and Yang IL-33 Regulates Metabolic Disorders
FIGURE 1 | The regulatory role of IL-33 in metabolic diseases. IL-33/ST2 axis regulates metabolic diseases through: (1) promoting AAM polarization; (2) regulating the
differentiation and functions of Treg and Th2; and (3) regulating the function of ILC2.
(46). Concordantly, the ST2+Tregs population is with a
higher expression of activated marker ICOS and CD44
(38). Thus, IL-33 plays a protective role in adipose tissue
inflammation through directly and indirectly regulating Tregs
It has also been reported that increasing severity of insulin
resistance and microalbuminuria is strongly correlated with the
decreased level of IL-33 in patients with diabetic nephropathy,
where an enhanced Th1 and suppressed Th2 response is observed
(47). ST2 is selectively and stably expressed on the surface of
Th2 cells, and IL-33 can effectively induce the immune response
of Th2 cells and the expression of Th2 related cytokines IL-5
and IL-13 without increasing IFN-γexpression (48,49). These
studies suggest that the ST2/IL-33 axis is closely associated
with the Th1/Th2 response imbalance in the development of
diabetes. Atherosclerosis is characterized by the formation of
fibrotic plaques in the major arteries and increased Th1 immune
response, which leads to myocardinfal iarction and stroke (50,
51). It has been shown that Th1-to-Th2 shift can reduce the
development of atherosclerosis (52,53). Due to the effect of IL-
33 on Th2-type immune response, IL-33 exhibits a protective
role in the pathogenesis of atherosclerosis (54). Previous findings
also showed that the reduced level of IL-33 might increase the
risk of atherosclerosis development for certain individuals (55).
These data suggest a crucial role of IL-33 in the lipid metabolism
through regulating T cells differentiation.
Due to the vital role of IL-33 in the metabolic homeostasis, a
sound understanding of the production, regulation, and function
of IL-33 will facilitate the treatment of metabolic disorders.
The potential mechanisms (Figure 1) of IL-33/ST2 axis in the
metabolic disorders may include: (1) IL-33 promotes the AAM
polarization; (2) IL-33 regulates Tregs and Th2 differentiation
and function; and (3) IL-33 regulates the function of ILC2.
Notably, the AAM polarization induced by IL-33 depends on
Type 2 cytokines, which may be released from ILC2. However,
most studies in this area were mainly carried out on animal
models and there were limited clinical trials. To what extent IL-
33 contributes to metabolic disorders in humans still requires
further investigation.
LT and LY reviewed the literature and wrote the first draft. LY
finalized the manuscript. LT and LY have read and approved the
final manuscript.
This work was supported by the National Natural Science
Foundation of China 81700490 to LT.
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Conflict of Interest Statement: The authors declare that the research was
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Frontiers in Endocrinology | 5January 2019 | Volume 10 | Article 26
... However, the precise mechanism underlying obesity-induced inflammation remains incompletely understood. IL-33, a newly discovered cytokine in the interleukin-1 (IL-1) family, is associated with Th1 and Th2 immune responses, which has been shown to be broadly expressed in various tissues and play a significant role as an 'alarmin' of some diseases [9][10][11][12]. Several reports have shown that IL-33 is important for maintaining immune cell homeostasis in adipose tissue [6] as well as the involvement of adipose tissue microenvironment in the obesity-related inflammation and complications [13]. ...
... In addition, IL-33 promotes the beiging of white adipocytes and energy expenditure by activating group 2 innate lymphoid cells (ILC2s) in adipose tissue, contracting obesity and its related disorders [14][15][16]. Despite the beneficial effects as an anti-inflammatory factor [9][10][11]17], the double-edged sword effect of IL-33 in immunity and metabolism has gained growing attention [10,11,18]. Meanwhile, studies have also reported that IL-33 may play an undetermined role in obesity and its cardiovascular or diabetic complications since the specific role of IL-33 in the pathogenesis and development of several metabolic diseases seems to be inconsistent [9,[14][15][16][17]. ...
... In addition, IL-33 promotes the beiging of white adipocytes and energy expenditure by activating group 2 innate lymphoid cells (ILC2s) in adipose tissue, contracting obesity and its related disorders [14][15][16]. Despite the beneficial effects as an anti-inflammatory factor [9][10][11]17], the double-edged sword effect of IL-33 in immunity and metabolism has gained growing attention [10,11,18]. Meanwhile, studies have also reported that IL-33 may play an undetermined role in obesity and its cardiovascular or diabetic complications since the specific role of IL-33 in the pathogenesis and development of several metabolic diseases seems to be inconsistent [9,[14][15][16][17]. ...
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Background Interleukin-33 (IL-33) plays a pivotal role in regulating innate immune response and metabolic homeostasis. However, whether its circulating level is correlated with obesity and metabolic disorders in humans remains largely unknown. We aimed to address this gap by determining IL-33 serum level and its downstream type 2 inflammatory cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13) in overweight/obese population, and analyzing the specific associations between IL-33 and obesity metabolic phenotypes. Methods 217 subjects were enrolled and divided into three groups: healthy control (HC) subjects, metabolically healthy overweight/obese (MHOO) subjects and metabolically unhealthy overweight/obese (MUOO) subjects. Circulating levels of IL-33, IL-5 and IL-13 were measured using ELISA analyses. Multivariate regression analyses were further performed to determine the independent association between IL-33 and obesity metabolic phenotypes. Results Circulating levels of IL-33 were significantly elevated in subjects of MUOO group compared with HC group and MHOO group, while no significant difference was observed between the latter two groups in IL-33 levels. Consistent with this, serum levels of IL-5/13 were higher in the MUOO group compared with HC and MHOO groups. After adjusted for all confounders, MUOO phenotype was significantly associated with increased IL-33 serum levels (OR = 1.70; 95% CI 1.09–2.64; p = 0.019). With the MHOO group as the reference population, higher circulating level of IL-33 was also positively associated with MUOO phenotype after adjusting for confounders (OR = 1.50; 95% CI 1.20–1.88; p = 2.91E−4). However, there was no significant association between MHOO phenotype and IL-33 levels ( p = 0.942). Trend analysis further confirmed the positive correlation between MUOO phenotype and IL-33 level ( p for trend = 0.019). Additionally, IL-33 was significantly and positively correlated with diastolic blood pressure (DBP), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), neutrophil and IL-5 only in MUOO group, while inversely correlated with high density lipoprotein cholesterol (HDL-C) in MHOO subjects. Conclusion Circulating levels of IL-33 were significantly elevated in overweight/obese Chinese adults with metabolic disorders. Increased levels of IL-33 were positively associated with metabolically unhealthy overweight/obese phenotype and several metabolic syndrome risk factors.
... Importantly, IL-33, a newly identified member of the IL-1 cytokine family, plays a protective role against inflammation of adipose tissue by directly and indirectly regulating T-regulatory cells (Tregs) function. Further investigations are required to determine to which extent IL-33 contributes to metabolic disorders in humans [16]. ...
... Our study found that IL-33 mRNA expression was significantly decreased in all MetS groups compared with that in healthy controls, and this decrease was higher with the increase in MetS criteria (diabetic and hypertensive groups were lower than obese and dyslipidemia groups). Previous studies investigated the link between IL-33, an anti-inflammatory cytokine, and obesity [16]. IL-33 has a crucial role in lipid metabolism and exhibits a protective role in the pathogenesis of atherosclerosis and acute cardiovascular events [53]. ...
... Importantly, IL-33, a newly identified member of the IL-1 cytokine family, plays a protective role against inflammation of adipose tissue by directly and indirectly regulating T-regulatory cells (Tregs) function. Further investigations are required to determine to which extent IL-33 contributes to metabolic disorders in humans [16]. ...
... Our study found that IL-33 mRNA expression was significantly decreased in all MetS groups compared with that in healthy controls, and this decrease was higher with the increase in MetS criteria (diabetic and hypertensive groups were lower than obese and dyslipidemia groups). Previous studies investigated the link between IL-33, an anti-inflammatory cytokine, and obesity [16]. IL-33 has a crucial role in lipid metabolism and exhibits a protective role in the pathogenesis of atherosclerosis and acute cardiovascular events [53]. ...
Metabolic syndrome (MetS) has been associated with a chronic inflammation state; the specific causative etiology to the MetS will need further investigation. The present study aims to explore the levels and roles of pro- and anti-inflammatory biomarkers and antioxidant enzymes in MetS development. Subjects were divided into five groups: healthy controls; patients with dyslipidemia; patients with dyslipidemia and obesity; patients with dyslipidemia, obesity, and hypertension; patients with dyslipidemia, obesity, hypertension, and hyperglycemia. Antioxidant enzyme activities were dramatically decreased in MetS patients, whereas inflammatory marker levels were elevated. The levels of interleukin (IL)-8, IL-23, IL-33, nuclear factor kappa B (NF-κΒ), resistin, and nitric oxide were positively correlated to triglyceride, low-density lipoprotein-cholesterol, fasting plasma glucose, and glycosylated hemoglobin levels. Therefore, the data indicate that antioxidant enzymes, IL-8, IL-23, IL-33, NF-κΒ, and resistin might be used as tools to ameliorate and treat metabolic diseases.
... IL-33/ST2 is involved in various ocular diseases, including allergic eye disease, dry eye disease, uveitis, vitreoretinal disease, and neuromyelitis optica spectrum disorder [277,278], as reviewed by Qian et al. [279]. IL-33 also plays an important role in metabolic diseases, such as obesity and type 2 diabetes, which has been summarized by Tu et al. [280]. ...
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Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cyto-kine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an "alarmin" by binding to its receptor, suppression of tumorigen-icity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro-and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
... Moreover, IL-33 also plays an important role in immune regulation. It can regulate Tregs and Th2 differentiation and function and stimulate immune cells such as dendritic cells, macrophages and mast cells to produce inflammatory cytokines (24,26,27). In this study, IHC staining of IL-33 in human EAC tissues showed that IL-33 was mainly expressed in the cytoplasm in EAC and in the nucleus in adjacent normal epithelial cells. ...
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Background: The progression from chronic gastroesophageal reflux disease (GERD) to Barrett esophagus (BE) and esophageal adenocarcinoma (EAC) is an inflammatory-driven neoplastic change. Interleukin-33 (IL-33) has identified as a crucial factor in several inflammatory disorders and malignancies. Methods: The high-density tissue microarray of the human EAC was analyzed with IL-33 immunohistochemistry staining (IHC). By anastomosing the jejunum with the esophagus, the rat model of EAC with mixed gastroduodenal reflux was established. The expression of IL-33 was determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blot (WB), IHC and enzyme-linked immunosorbent assay (ELISA). Esophageal adenocarcinoma cells (OE19 and OE33) and human esophageal epithelial cells (HEECs) were used. Results: In the cytoplasm of human EAC tissue, IL-33 expression was substantially greater than in adjacent normal tissue. In rat model, the expression of IL-33 in the EAC group was considerably greater than in the control group, and this expression increased with the upgrade of pathological stage. In in vitro experiment, the mRNA and protein levels of IL-33 were considerably greater in OE19 and OE33 than in HEECs. The stimulation of IL-33 enhanced the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OE19 and OE33, but soluble ST2 (sST2) inhibited these effects. IL-33 stimulated the release of IL-6 by OE19 and OE33 cells. Conclusion: This study demonstrated the overexpression of IL-33 in the transition from GERD to EAC and that IL-33 promoted carcinogenesis in EAC cells through ST2. IL-33 might be a possible preventive target for EAC.
... The PW with MS and higher levels of circulating IL-15 showed also higher levels of IL-1b, IL-5, IL-6, IL-10, IL-13, and IL-33. Higher levels of these cytokines are also thought to contribute (positively or negatively) to RI [7,14,27,28]. Even when these cytokines were considered in the statistical model, higher The most interesting finding is that PW with MS and higher levels of circulating IL-15 showed improved IR when compared with those with MS but a lower level of circulating IL-15. ...
Objective: To determine if higher levels of circulating interleukin (IL)-15 are positively associated with improvement in insulin resistance in postmenopausal women (PW) with metabolic syndrome (MS). Methods: According to the median value of IL-15 at baseline, PW older than or equal to 45 years were divided into two groups: higher (n = 43) and lower (n = 42) IL-15. There was a 9-month follow-up period with clinical assessments at baseline and at 9 months (criteria of metabolic syndrome, body fat, and insulin resistance). Insulin resistance (IR) was calculated according to the Homeostasis Model Assessment-estimated insulin resistance (HOMA-IR). For IL-1β, IL-6, IL-10, IL-13, IL-33, IL-15, and TNF-α was determined using immunoassay Magnetic Bead Panel. Results: There was an interaction between the time and group only for insulin (p = .008) and HOMA-IR (p = .024). After adjusting for confounding variables (clinical and ILs), the HOMA-IR (p = .006) and insulin (p = .003) were lower in the higher-IL-15 group [HOMA-IR: 2.2 (95% CI: 1.9-2.5) and insulin: 9.1 µIU/mL (95% CI: 7.9-10.3)] when compared to the lower-IL-15 group [HOMA-IR: 3.1 (95% CI: 2.6-3.6) and insulin: 12.9 (95% CI: 11.1-14.9)] after 9 months of follow-up. Conclusion: Higher levels of circulating IL-15 are positively associated with improvements in IR in PW with MS.
... Activated IL-33 binds to a co-receptor, a heterodimer composed of ST2 and IL1RAP, and initiates inflammatory pathways [6]. In addition, IL-33 recruits signal adapters and kinases to activate transcription factors in tumour cells, which produce the tumourassociated inflammatory microenvironment [7]. ...
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Background Interleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action. Methods In this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student’s t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software. Results The IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69⁺ CD8⁺ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC. Conclusions Taken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.
... IL-33, a cytokine related to IL-1, has a role both in inflammation, and in metabolism (135,136). IL-33 binds to receptor, ST2. Levels of IL-33 are reduced in ALS, and levels of soluble ST2 are increased in ALS (84). ...
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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.
Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family which plays roles in the nucleus as a nuclear factor and is released by damaged or necrotic cells to act as a cytokine. It can be released via damaged or necrotic cells and functions as a cytokine. The released IL-33 activates the downstream NF-κB and MAPKs signaling pathways through the isomers of the specific receptor ST2 and the interleukin-1 receptor accessory protein (IL-1RAcP), resulting in danger signals and the activated multiple immune responses. IL-33 is abnormally expressed in various tumors and involves in tumorigenesis, development, and metastasis. Moreover, IL-33 can play both pro-tumor and anti-tumor roles in the same type of tumor.
Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.
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Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout.
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Type 2 innate lymphoid cells (ILC2) in lungs produce interleukin (IL)-5 and IL-13 in response to IL-33 and may contribute to the development of allergic diseases such as asthma. However, little is known about negative regulators and effective inhibitors controlling ILC2 function. Here, we show that soluble ST2, a member of the IL-1 receptor family, suppresses the effect of IL-33 on lung ILC2 in vitro. Stimulation with IL-33 to naïve ILC2 induced morphological change and promoted cell proliferation. In addition, IL-33 upregulated expression of cell surface molecules including IL-33 receptor and induced production of IL-5 and IL-13, but not IL-4. Pretreatment with soluble ST2 suppressed IL-33-mediated responses of ILC2. The results suggest that soluble ST2 acts as a decoy receptor for IL-33 and protects ILC2 from IL-33 stimulation.
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Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4 T cells which produce type 2 cytokines can be generated via IL-4-dependent and-independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4 T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-B but not the induction of GATA3 or T-bet. In vivo, ST2 / mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4 / mice. Finally, adoptive transfer of IL-33-polarized IL-5 IL-4 T cells triggered airway inflammation in naive IL-4 / mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4.
In obesity, IL-13 overcomes insulin resistance by promoting anti-inflammatory macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine. In this study, we show that IL-13Rα2 is markedly elevated in adipose tissues of obese mice. Mice deficient in IL-13Rα2 had high expression of IL-13 response markers in adipose tissue, consistent with increased IL-13 activity at baseline. Moreover, exposure to the type 2 cytokine-inducing alarmin, IL-33, enhanced serum and tissue IL-13 concentrations and elevated tissue eosinophils, macrophages, and type 2 innate lymphoid cells. IL-33 also reduced body weight, fat mass, and fasting blood glucose levels. Strikingly, however, the IL-33-induced protection was greater in IL-13Rα2-deficient mice compared with wild-type littermates, and these changes were largely attenuated in mice lacking IL-13. Although IL-33 administration improved the metabolic profile in the context of a high fat diet, it also resulted in diarrhea and perianal irritation, which was enhanced in the IL-13Rα2-deficient mice. Weight loss in this group was associated with reduced food intake, which was likely related to the gastrointestinal effects. These findings outline both potentially advantageous and deleterious effects of a type 2-skewed immune response under conditions of metabolic stress, and identify IL-13Rα2 as a critical checkpoint in adipose tissues that limits the protective effects of the IL-33/IL-13 axis in obesity.
Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.
Key Points IL-25, IL-33, and TSLP induce distinct activation profiles in ILC2s. IL-2 further amplifies their response and induces an NK-like phenotype. ILC2 plasticity is observed in serum-free media even when in the presence of IL-25, IL-33, and TSLP, and absence of either IL-1β or IL-12.
Interleukin (IL)-33 is a member of the IL-1 family. Serum levels of IL-33 are increased in inflammatory bowel diseases (IBD), suggesting that IL-33 is involved in the pathogenesis of IBD, although its role is not clear. In this study, we investigated the role of IL-33 in the regulation of T-helper (Th) cell and B cell responses in mesenteric lymph nodes (MLN) in mice with dextran sulfate sodium (DSS)-induced colitis. Here, we showed that IL-33-treated mice were susceptible to DSS-induced colitis as compared with PBS-treated mice. The production of spontaneous inflammatory cytokines production by macrophages or dendritic cells (DC) in MLN significantly increased, and the responses of Th2, regulatory T cells (Treg) and regulatory B cells (Breg) were markedly upregulated, while Th1 responses were significantly downregulated in MLN of IL-33-treated mice with DSS-induced colitis. Our results demonstrate that IL-33 contributes to the pathogenesis of DSS-induced colitis in mice by promoting Th2 responses, but suppressing Th1 responses, in MLN. Moreover, IL-33 treatment increased Breg and Treg responses in MLN in mice with DSS-induced colitis. Therefore, modulation of IL-33/ST2 signaling is implicated as a novel biological therapy for inflammatory diseases associated with Th1 responses.
IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-γ production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L-dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development.