Article

Palmitic acid induces IP-10 expression in human macrophages via NF-??B activation

Authors:
Article

Palmitic acid induces IP-10 expression in human macrophages via NF-??B activation

If you want to read the PDF, try requesting it from the authors.

Abstract

It is now recognized that cross-talk between adipocytes and adipose tissue stromal cells such as macrophages contributes to local and systemic inflammation. One factor from adipocytes that may participate in this interaction and that is frequently elevated in inflammatory conditions such as obesity, insulin resistance, and type 2 diabetes is free fatty acids (FFA). To investigate the potential for FFA to enhance macrophage inflammation, we exposed U937 macrophages to physiological levels (150 microM) of FFA. Palmitic acid (PA), the predominant saturated FFA released from adipose tissue, but not unsaturated FFA, induced an approximately 6-fold (p<0.05) increase in IP-10 gene expression (and 2- to 4-fold increases in IL-8, MCP-1, COX-2, and MIG). PA also induced an approximately 2-fold increase (p<0.05) in active NF-kappaB, and two structurally distinct NF-kappaB inhibitors effectively blocked PA-induced IP-10 gene expression. Conditioned medium from PA-treated cells increased lymphocyte migration 41% (p<0.05) which was significantly reduced by IP-10-neutralizing antibody. These results suggest that elevated concentrations of PA commonly present in obese and insulin resistant individuals can increase NF-kappaB-mediated expression of IP-10 in macrophages. These events in turn may lead to an increasing feed-forward loop of chronic inflammation.

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.

... Taken together, the majority of in vitro studies have shown that PA and SA induce a proinflammatory profile in adipocytes. Similar results with these longchain SFAs are also demonstrated in other tissues [22,[25][26][27][28][29][30][31][32][33]. Specifically, PA-and SA-activated TLR-4 receptor [22,34] and increased TNF-A, IL-6, IL-8, and IL-1B mRNA expression and secretion in monocyte [34][35][36][37] and macrophage [28] cell models. ...
... OA also decreased resistin gene expression and increased adiponectin gene expression [42]. In macrophages, OA had a neutral effect on inflammatory marker release [27,41,43] and could prevent the activation of the NLRP3 inflammasome [37]. Those data suggest an anti-inflammatory role of OA in adipocytes and macrophages. ...
... However, LA does not have clear effects on inflammatory profiles in cell studies. Adipocytes incubated with LA increase TNF-A and IL-6 expression [48] as well as a decreased adiponectin gene expression [19], whereas endothelial cells [38,44,49,50] and macrophages [27,[51][52][53] incubated with LA did not change inflammation levels. LA may also have a beneficial effect on inflammation by inhibiting the effect of PA [23,45,54]. ...
Article
Dairy products contain milkfat, proteins, minerals, vitamin D and other bioactive nutrients that have the potential to contribute to the association observed between increased dairy intake and a decreased risk of inflammation. The objective of this paper is to review the role of dairy bioactive molecules including: dairy fat, proteins, micronutrients and vitamins on inflammation markers in adipose, macrophage and vascular tissues, which play a key role in the regulation of inflammation. A review was conducted to identify current scientific literature on dairy nutrients and inflammation in cell studies published until November 2014. The majority of saturated fatty acids (FAs) activate pro-inflammatory markers. Therefore, other dairy FAs or components may offset these harmful effects. Protein and amino acid composition of dairy products may have anti-inflammatory action. Magnesium may have beneficial effects on inflammatory profile; on the contrary, studies on vitamin D demonstrate conflicting results. In conclusion, numerous studies assessed the effects of individual or mixtures of FAs on inflammatory markers; yet, there is far less research on the effects of other dairy bioactive nutrients. The exact bioactive molecule or combination of these molecules in dairy products which underlies the inverse association between dairy intake and inflammation remains to be elucidated.This article is protected by copyright. All rights reserved
... Gesättigte Fettsäuren im Plasma scheinen an der Ausbildung einer unterschwelligen, chronischen Entzündung beteiligt zu sein. In Monozyten-und Makrophagenzellkulturmodellen stimulierten gesättigte Fettsäuren wie Palmitat, im Gegensatz zu ungesättigten Fettsäuren, die mRNA-Expression und Proteinproduktion der pro-inflammatorischen Zytokine TNFα [30,35,[134][135][136][137][138][139][140][141][142], IL-1 β [136,[142][143][144][145], IL-6 [135,[138][139][140]142], IL-8 [136,137,139,146,147] und CCL2 [142,146,147]. Die zugrundeliegenden Mechanismen sind jedoch noch unzureichend erforscht. ...
... Gesättigte Fettsäuren im Plasma scheinen an der Ausbildung einer unterschwelligen, chronischen Entzündung beteiligt zu sein. In Monozyten-und Makrophagenzellkulturmodellen stimulierten gesättigte Fettsäuren wie Palmitat, im Gegensatz zu ungesättigten Fettsäuren, die mRNA-Expression und Proteinproduktion der pro-inflammatorischen Zytokine TNFα [30,35,[134][135][136][137][138][139][140][141][142], IL-1 β [136,[142][143][144][145], IL-6 [135,[138][139][140]142], IL-8 [136,137,139,146,147] und CCL2 [142,146,147]. Die zugrundeliegenden Mechanismen sind jedoch noch unzureichend erforscht. ...
... Die zugrundeliegenden Mechanismen sind jedoch noch unzureichend erforscht. Es wird vermutet, dass die Aktivierung des TLR4, welcher vor allem für die Bindung des bakteriellen LPS bekannt ist [148,149], bei der Wirkung von freien Fettsäuren eine entscheidende Rolle spielt [64,136,140,146,150]. ...
Thesis
Full-text available
Insulinresistenz ist ein zentraler Bestandteil des metabolischen Syndroms und trägt maßgeblich zur Ausbildung eines Typ-2-Diabetes bei. Eine mögliche Ursache für die Entstehung von Insulinresistenz ist eine chronische unterschwellige Entzündung, welche ihren Ursprung im Fettgewebe übergewichtiger Personen hat. Eingewanderte Makrophagen produzieren vermehrt pro-inflammatorische Mediatoren, wie Zytokine und Prostaglandine, wodurch die Konzentrationen dieser Substanzen sowohl lokal als auch systemisch erhöht sind. Darüber hinaus weisen übergewichtige Personen einen gestörten Fettsäuremetabolismus und eine erhöhte Darmpermeabilität auf. Ein gesteigerter Flux an freien Fettsäuren vom Fettgewebe in andere Organe führt zu einer lokalen Konzentrationssteigerung in diesen Organen. Eine erhöhte Darmpermeabilität erleichtert das Eindringen von Pathogenen und anderer körperfremder Substanzen in den Körper. Ziel dieser Arbeit war es, zu untersuchen, ob hohe Konzentrationen von Insulin, des bakteriellen Bestandteils Lipopolysaccharid (LPS) oder der freien Fettsäure Palmitat eine Entzündungsreaktion in Makrophagen auslösen oder verstärken können und ob diese Entzündungsantwort zur Ausbildung einer Insulinresistenz beitragen kann. Weiterhin sollte untersucht werden, ob Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind, die Produktion des Prostaglandins (PG) E2 begünstigen können und ob dieses wiederum die Entzündungsreaktion und seine eigene Produktion in Makrophagen regulieren kann. Um den Einfluss dieser Faktoren auf die Produktion pro-inflammatorischer Mediatoren in Makrophagen zu untersuchen, wurden Monozyten-artigen Zelllinien und primäre humane Monozyten, welche aus dem Blut gesunder Probanden isoliert wurden, in Makrophagen differenziert und mit Insulin, LPS, Palmitat und/ oder PGE2 inkubiert. Überdies wurden primäre Hepatozyten der Ratte isoliert und mit Überständen Insulin-stimulierter Makrophagen inkubiert, um zu untersuchen, ob die Entzündungsanwort in Makrophagen an der Ausbildung einer Insulinresistenz in Hepatozyten beteiligt ist. Insulin induzierte die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien wahrscheinlich vorrangig über den Phosphoinositid-3-Kinase (PI3K)-Akt-Signalweg mit anschließender Aktiverung des Transkriptionsfaktors NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells). Die dabei ausgeschütteten Zytokine hemmten in primären Hepatozyten der Ratte die Insulin-induzierte Expression der Glukokinase durch Überstände Insulin-stimulierter Makrophagen. Auch LPS oder Palmitat, deren lokale Konzentrationen im Zuge des metabolischen Syndroms erhöht sind, waren in der Lage, die Expression pro-inflammatorischer Zytokine in Makrophagen-artigen Zelllinien zu stimulieren. Während LPS seine Wirkung, laut Literatur, unbestritten über eine Aktivierung des Toll-ähnlichen Rezeptors (toll-like receptor; TLR) 4 vermittelt, scheint Palmitat jedoch weitestgehend TLR4-unabhängig wirken zu können. Vielmehr schien die de novo-Ceramidsynthese eine entscheidene Rolle zu spielen. Darüber hinaus verstärkte Insulin sowohl die LPS- als auch die Palmitat-induzierte Ent-zündungsantwort in beiden Zelllinien. Die in Zelllinien gewonnenen Ergebnisse wurden größtenteils in primären humanen Makrophagen bestätigt. Desweiteren induzierten sowohl Insulin als auch LPS oder Palmitat die Produktion von PGE2 in den untersuchten Makrophagen. Die Daten legen nahe, dass dies auf eine gesteigerte Expression PGE2-synthetisierender Enzyme zurückzuführen ist. PGE2 wiederum hemmte auf der einen Seite die Stimulus-abhängige Expression des pro-inflammatorischen Zytokins Tumornekrosefaktor (TNF) α in U937-Makrophagen. Auf der anderen Seite verstärkte es jedoch die Expression der pro-inflammatorischen Zytokine Interleukin- (IL-) 1β und IL-8. Darüber hinaus verstärkte es die Expression von IL-6-Typ-Zytokinen, welche sowohl pro- als auch anti-inflammatorisch wirken können. Außerdem vestärkte PGE2 die Expression PGE2-synthetisierender Enzyme. Es scheint daher in der Lage zu sein, seine eigene Synthese zu verstärken. Zusammenfassend kann die Freisetzung pro-inflammatorischer Mediatoren aus Makro-phagen im Zuge einer Hyperinsulinämie die Entstehung einer Insulinresistenz begünstigen. Insulin ist daher in der Lage, einen Teufelskreis der immer stärker werdenden Insulin-resistenz in Gang zu setzen. Auch Metabolite und Signalsubstanzen, deren Konzentrationen beim metabolischen Syndrom erhöht sind (zum Beispiel LPS, freie Fettsäuren und PGE2), lösten Entzündungsantworten in Makrophagen aus. Das wechselseitige Zusammenspiel von Insulin und diesen Metaboliten und Signalsubstanzen löste eine stärkere Entzündungsantwort in Makrophagen aus als jeder der Einzelkomponenten. Die dadurch freigesetzten Zytokine könnten zur Manifestation einer Insulinresistenz und des metabolischen Syndroms beitragen.
... Another limitation was that DHA-containing oil had higher saturated fatty acids: lauric, myristic and palmitic, but lower linoleic and oleic acids compared with SO administered to the control group. In this regard, it has been reported that saturated fatty acids had the potential to activate the signaling cascade to increase pro-inflammatory cytokines [50,51] responsible for peripheral nociceptive induction of pain, while linoleic and oleic acid had no effect [50] . Conversely, DHA ameliorates pro-inflam-matory cytokines [52,53]. ...
... Another limitation was that DHA-containing oil had higher saturated fatty acids: lauric, myristic and palmitic, but lower linoleic and oleic acids compared with SO administered to the control group. In this regard, it has been reported that saturated fatty acids had the potential to activate the signaling cascade to increase pro-inflammatory cytokines [50,51] responsible for peripheral nociceptive induction of pain, while linoleic and oleic acid had no effect [50] . Conversely, DHA ameliorates pro-inflam-matory cytokines [52,53]. ...
Article
Full-text available
Background: Neonates undergoing surgery require analgesic medication to ameliorate acute pain. These medications produce negative side effects. Docosahexaenoic acid (DHA) has an antinociceptive effect in animals, but this has not been evaluated in human neonates. We evaluated the DHA effect on cumulative dose and duration of analgesics administered to neonates undergoing cardiovascular surgery. Methods: A secondary analysis was performed with data from a clinical trial, in which enteral DHA was administered perioperatively compared with sunflower oil (SO). Present study assessed the antinociceptive effect of DHA by measuring the cumulative dose and duration of analgesics administered during postoperative stay in a neonatal intensive care unit. Multivariate linear regression models were performed. Results: Seventeen neonates received DHA and 18 received SO in the control group. Compared with the control group, the DHA group received lower cumulative dose (14.6 ± 2.2 vs. 25.2 ± 4.8 μg/kg, p = 0.029) and shorter duration of buprenorphine (2 days (1-8) vs. 4.5 days (1-12); p = 0.053). After adjusting for confounders, the DHA group received significantly lesser buprenorphine (β = -27 μg/kg, p = 0.028; R2 model = 0.90) for shorter duration (β = -9 days, p = 0.003; R2 model = 0.94). No differences in fentanyl or ketorolac were detected. Conclusions: Buprenorphine administration was reduced in neonates who received DHA, suggesting that DHA likely has analgesic effects.
... Acyl-coenzyme A oxidase (Acox1), a rate-limiting enzyme in the peroxisomal β-oxidation pathway, is responsible for catabolism of very long-chain fatty acids. Saturated long-chain fatty acids are known to activate inflammatory and innate immune responses in immune cells (22)(23)(24). Altered Acox1 function is associated with spontaneous liver damage in humans (25)(26)(27). In fact, patients with pseudoneonatal adrenoleukodystrophy, a rare inflammatory neurodegenerative disease caused by Acox1 deficiency, exhibit hepatomegaly due to impairment of peroxisomal fatty acid β-oxidation of very long-chain fatty acids (28). ...
... Similar to HFHCD Acox1 Lampe1 young mice, tumor-bearing, 1-year-old, Acox1 Lampe1 mice exhibited increased hepatic chemokine expression (e.g., Ccl2, Ccl3, Ccl4, Ccl22, and Cxcl10; Supplemental Figure 9). Further, although HFHCD feeding robustly induced expression of genes considered markers (8,12,16,23, and 59 weeks of age) and histopathological changes in chow-fed Acox1 Lampe1 mice. Acox1 Lampe1 mice display steatosis, increasing inflammation, and liver cell injury over time with development of hepatocellular tumors at 59 weeks of age. ...
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression.
... On this basis, the differences found in the FFA composition between control and necrotic adipose tissues should also be considered. The previous studies have concluded an enhancement of the inflammatory response to saturated FFAs [34][35][36]. In line with the pro-inflammatory effects demonstrated for palmitic acid (PA) in astrocytes [9] and macrophages [34], we suggest that the increased PA content found in necrotic fat could act as a contributing factor to the acinar inflammatory response. ...
... The previous studies have concluded an enhancement of the inflammatory response to saturated FFAs [34][35][36]. In line with the pro-inflammatory effects demonstrated for palmitic acid (PA) in astrocytes [9] and macrophages [34], we suggest that the increased PA content found in necrotic fat could act as a contributing factor to the acinar inflammatory response. Anti-and pro-inflammatory effects have been reported for MUFAs [8] and PUFAs [6,10,36], respectively. ...
Article
Lipids play a role in acute pancreatitis (AP) progression. We investigate the ability of pancreatic acinar cells to trigger inflammatory response in the presence of lipid compounds generated in necrotic areas of peripancreatic adipose tissue (AT) during severe AP. Lipids from AT of either control rats (AT-C) or necrotic areas (AT-N) of rats with AP induced by 5% sodium taurocholate were analyzed by HPLC-mass spectrometry. We evaluated the acinar inflammatory response to total lipids as well as to either the free fatty acid (FFA) fraction or their chlorinated products (Cl-FFA). mRNA expression of inflammatory mediators as well as the activation of MAPKs, NF-κB and STAT-3 were analyzed in pancreatic acini. Myeloperoxidase (MPO) activity, as an inducer of Cl-FFA generation, was also analyzed in AT. MPO activity significantly increased in AT-N. AP induced changes in lipid composition of necrotic fat, such as increase in FFA and phospholipid (PL) content, generation of Cl-FFA and increases in saturated FFA and in the poly-: mono-unsaturated FFA ratio. Total lipids of AT-N induced overexpression of monocyte chemoattractant protein-1 (MCP-1) and P-selectin in pancreatic acini as well as MAPKs phosphorylation and activation of NF-κB and STAT3. FFA, but not Cl-FFA, overexpressed MCP-1 in acinar cells. We conclude that FFA are capable of upregulating inflammatory mediators in pancreatic acini and given they are highly produced during AP, mainly may contribute to the inflammatory response triggered in acinar cells by fat necrosis. No role is played by Cl-FFA generated as a result of neutrophil infiltration.
... DHA-containing oil had higher lauric, myristic and palmitic acid, but lower oleic and linoleic acid. Lauric, myristic and palmitic acids have the potential to activate NFκB and increase inflammatory cytokines in macrophages [37,38] , whereas linoleic and oleic acid had no effect [37] . Nonetheless, DHA may prevent or ameliorate their actions on inflammatory signaling attenuating inflammatory cytokines [19,20,39] ; thus, we do not expect that the concentration of these fatty acids would have biased the results. ...
... DHA-containing oil had higher lauric, myristic and palmitic acid, but lower oleic and linoleic acid. Lauric, myristic and palmitic acids have the potential to activate NFκB and increase inflammatory cytokines in macrophages [37,38] , whereas linoleic and oleic acid had no effect [37] . Nonetheless, DHA may prevent or ameliorate their actions on inflammatory signaling attenuating inflammatory cytokines [19,20,39] ; thus, we do not expect that the concentration of these fatty acids would have biased the results. ...
Article
Full-text available
Background: Neonates undergoing surgery are at risk for uncontrolled inflammatory response and adverse clinical outcomes. Docosahexaenoic acid (DHA) ameliorates inflammation, improving clinical outcomes. However, its effect has not been evaluated in neonates undergoing surgery. We evaluated the effect of DHA on markers of inflammation and clinical outcomes in neonates undergoing surgery. Methods: A double-blind clinical trial evaluated the effect of enteral DHA (DHA group) versus sunflower oil (SO group) perioperatively administered in neonates scheduled for cardiovascular surgery. Inflammation was evaluated by percentage of cells+ for cytokines and CD69 in mononuclear cells at baseline, 24 h and 7 days post surgery. Clinical outcomes measured were sepsis, organ dysfunctions (ODs), length of stay in intensive care and bleeding. Repeated measures analysis of variance and logistic regression were applied. Results: Sixteen neonates received DHA and 18 received SO. Cells+ from neonates in the DHA group showed an early increase in receptor antagonist of interleukin (IL)-1+ (IL-1ra+) and IL-10+ and a late decrease in IL-6+. IL-1β+ and IL-10+ changes were different between groups. After adjusting for confounders, less cells from DHA group were IL-1β+, IL-6+, IL-1ra+ and IL-10+. DHA group presented less sepsis, ODs and shorter stay, but no difference in CD69+CD4+ cells or bleeding between groups. Conclusions: Administration of enteral DHA ameliorates markers of inflammation and improves clinical outcomes in surgical neonates.
... Our VLDL lipolysis products recently have been characterized, and palmitic acid is the most abundantly released nonesterified fatty acid by bovine LpL (40). Long-chain saturated fatty acids, such as palmitic acid, have been shown to induce TNF␣, IL-1␤, and IL-8 secretion and mRNA expression from macrophages by activation of NFB through Akt and AP-1 through p38 and JNK (17,21,23). Therefore, the proinflammatory effects seen after treatment with the FFA fraction most likely reflect saturated fatty acid treatment, although recent data suggest that other fatty acid classes may be involved (25,33). ...
Article
Full-text available
Postprandial lipemia is characterized by a transient increase in circulating triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL), and has been shown to activate monocytes in vivo. Lipolysis of VLDL releases remnant particles, phospholipids, monoglycerides, diglycerides, and fatty acids in close proximity to endothelial cells and monocytes. We hypothesized that postprandial VLDL lipolysis products could activate and recruit monocytes by increasing monocyte expression of pro-inflammatory cytokines and adhesion molecules, and that such activation is related to the development of lipid droplets. Freshly isolated human monocytes were treated with VLDL lipolysis products (2.28 mmol/l TG + 2 U/mL lipoprotein lipase), and monocyte adhesion to a primed endothelial monolayer was observed using a parallel plate flow chamber coupled with a CCD camera. Treated monocytes showed more rolling and adhesion than controls, and an increase in transmigration between endothelial cells. The increased adhesive events were related to elevated expression of key integrin complexes including Mac-1 (CD11b/CD18), CR4 (CD11c/CD18) and VLA-4 (CD49d/CD29) on treated monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) and THP-1 monocytes with VLDL lipolysis products increased expression of TNFα, IL-1β, and IL-8 over controls, with concurrent activation of NFkB and AP-1. NFκB and AP-1-induced cytokine and integrin expression was dependent on ERK and Akt phosphorylation. Additionally, fatty acids from VLDL lipolysis products induced ERK2-dependent lipid droplet formation in monocytes, suggesting a link to inflammatory signaling pathways. These results provide novel mechanisms for postprandial monocyte activation by VLDL lipolysis products, suggesting new pathways and biomarkers for chronic, intermittent vascular injury.
... Such acute stress signals can be rather diverse. Even non-physiological concentrations of nutrients including free fatty acids [28,29] and even elevated salt concentrations [30,31] can lead to acute changes of the macrophage activation state. Moreover, one also needs to consider significant influx of monocyte-derived macrophages that might be actually the main force reacting towards the inflammatory stimuli [21]. ...
Article
Cellular activation is mainly defined as the response of a cell to exogenous signals eventually leading to changes in protein expression and cellular function. Originally, macrophage activation was mainly associated with phagocytic function. Later other effector functions such as cytokine secretion, upregulation of cell surface receptors came into focus. For a while macrophage activation was classified as being either pro-inflammatory or anti-inflammatory and certain signal transduction pathways were associated with these two conditions. Most recent findings on transcriptional and epigenetic level, however, suggest that the molecular features of macrophage activation are significantly more complex. Here, we will introduce a novel and integrative model of macrophage activation. Albeit recognizing that macrophage activation cannot be reduced to nuclear processes, we will focus in this review on the most recent findings concerning transcriptional and epigenetic regulation of macrophage activation. Understanding the complexity of the central regulatory mechanisms in the nucleus will form a foundation for deciphering all the different effector functions that are associated with macrophage activation.
... Recently, the monounsaturated oleic acid was found to inhibit LPS-induced iNOS and COX-2 expression through blocking p38 and NF-κB signaling pathways in BV2 murine microglia (Oh et al., 2009). Palmitic acid has been shown to trigger inflammation in cultured human macrophages (Laine et al., 2007) and increasing TNF-α and IL-6 production via p38 and ERK activation in astrocytes cells (Gupta et al., 2012). However, ω-3 fatty acids could act in a dosedependent manner preventing the palmitic acid-induced inflammatory responses in astrocytes (Gupta et al., 2012). ...
Article
The anti-inflammatory properties of the supercritical fluid extract of Ishige okamurae (SFEIO) on lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. The lipid profile of the SFEIO, reviled the presence of palmitic acid (220.2 mg/g), linoleic acid (168.0 mg/g), and oleic acid (123.0 mg/g). SFEIO was found to exert it’s anti-inflammatory effects through inhibiting nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 production in LPS-stimulated RAW 264.7 cells, without inducing cytotoxicity. SFEIO did not effect on the LPS-induced p38 kinase phosphorylation, whereas it attenuated the extracellular-related signaling kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation. Furthermore, SFEIO inhibited the LPS-induced IκB-α degradation and p50 NF-κB activation. These results suggest that SFEIO exerts its anti-inflammatory effects in LPS-activated RAW 264.7 cells by down-regulating the activation of ERK, JNK, and NF-κB.
... Notably, stimulation of adipocytes with LPS causes lipolysis, insulin resistance, and secretion of proinflammatory cytokines and chemokines [10]. LPS binding to toll-like receptors (TLR)s triggers an inflammatory signaling cascade involving mitogen activated protein kinases (MAPK)s and nuclear factor kappa B (NF-κB) [11]. Activation of these proteins increases the transcription of proinflammatory genes. ...
... Miao et al. [2015] recently found out that "stearic acid induces the production of proinflammatory cytokines partly through activation of lactate-HIF1a pathway in chondrocytes." Research has also shown that lauric and palmitic acids can trigger inflammation in cultured macrophages and also regulates the amyloid processing in neurons and astrocytes [Patil and Chan, 2005;Patil et al., 2006;Laine et al., 2007]. In meniscus cells, palmitate treatment increased the expression of both a pro-apoptotic molecule CHOP and cleaved caspase-3 [Haywood and Yammani, 2016]. ...
Article
Full-text available
Osteoarthritis is a progressive, age-related disease characterized by the degradation of the cartilage, abnormal bone remodelling, and joint pain eventually leading to disability. The occurrence of clinically diagnosed OA and the incidence of disability show geographic variations, which suggests that lifestyle and factors such as diet play a vital role in the formation and progression of OA. Obesity is associated with a state of low-grade inflammation and increased plasma concentrations of fatty acids such as the saturated fatty acids (SFA). Importantly, obesity is a major risk factor for the development of OA in both weight-bearing and non-weight-bearing joints. Further, obese individuals bear the full brunt of OA which poses a huge health, social and economic problem, and hence it is essential to increase our understanding of OA and obesity to improve patient care and decrease disease progression. Hence, the current state of knowledge on the relationship between obesity and OA is reviewed, especially the influence of different diets. In particular, we emphasise the role and mechanisms of SFA to cause or worsen OA. This article is protected by copyright. All rights reserved
... Recently, the monounsaturated oleic acid was found to inhibit LPS-induced iNOS and COX-2 expression through blocking p38 and NF-κB signaling pathways in BV2 murine microglia (Oh et al., 2009). Palmitic acid has been shown to trigger inflammation in cultured human macrophages (Laine et al., 2007) and increasing TNF-α and IL-6 production via p38 and ERK activation in astrocytes cells (Gupta et al., 2012). However, ω-3 fatty acids could act in a dosedependent manner preventing the palmitic acid-induced inflammatory responses in astrocytes (Gupta et al., 2012). ...
Article
Full-text available
The anti-inflammatory properties of the supercritical fluid extract of Ishige okamurae (SFEIO) on lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages.The lipid profile of the SFEIO, reviled the presence of palmitic acid (220.2 mg/g), linoleic acid (168.0 mg/g), and oleic acid (123.0 mg/g).SFEIO was found to exert it’s anti-inflammatory effects through inhibiting nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 production in LPS-stimulated RAW 264.7 cells, without inducing cytotoxicity.SFEIO did not effect on the LPSinduced p38 kinase phosphorylation, whereas it attenuated the extracellular-related signaling kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation.Furthermore, SFEIO inhibited the LPS-induced IκB-α degradation and p50 NF-κB activation.These results suggest that SFEIO exerts its anti-inflammatory effects in LPSactivated RAW 264.7 cells by down-regulating the activation of ERK, JNK, and NF-κB. © 2016, Leibniz Research Centre for Working Environment and Human Factors.All rights reserved.
... In support of this hypothesis, supplementation with palmitate, one of the major FFAs released from the adipose tissue, caused recruitment of monocytes to hypertrophied adipocytes by inducing MCP-1 production via JNK and NF-κB activation [3]. Similarly, palmitate increased inflammatory gene expression in human macrophages by an NF-κB-dependent mechanism [50]. An important component of these FFA-induced activation events are the pattern recognition receptors, toll-like receptor-2 (TLR2) and TLR4. ...
Article
Full-text available
There is increasing evidence showing that chronic inflammation is an important pathogenic mediator of the development of type 2 diabetes (T2D). It is now generally accepted that tissue-resident macrophages play a major role in regulation of tissue inflammation. T2D-associated inflammation is characterized by an increased abundance of macrophages in different tissues along with production of inflammatory cytokines. The complexity of macrophage phenotypes has been reported from different human tissues. Macrophages exhibit a phenotypic range that is intermediate between two extremes, M1 (pro-inflammatory) and M2 (anti-inflammatory). Cytokines and chemokines produced by macrophages generate local and systemic inflammation and this condition leads to pancreatic β-cell dysfunction and insulin resistance in liver, adipose and skeletal muscle tissues. Data from human and animal studies also suggest that macrophages contribute to T2D complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases through cell-cell interactions and the release of pro-inflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. In this review we focus on the functions of macrophages and the importance of these cells in the pathogenesis of T2D. In addition, the contribution of macrophages to diabetes complications such as nephropathy, neuropathy, retinopathy and cardiovascular diseases is discussed.
... In particular, aberrant CD4 + T cell responses to antigens derived from the resident microbiota have been implicated in the pathogenesis of IBD [31,86] . Pretreatment with the ethanolic extract of P. vulgaris decreased production of CXCL10 and CXCL9, two proteins that are induced by IFNγ and are chemotactic for T cells (Table 2) [79,87] . These chemokines and other cytokines participate in inflammatory feedback loops that may be interrupted by treatment with the ethanolic extract of P. vulgaris. ...
Article
Aim: To investigate the ability of a Prunella vulgaris (P. vulgaris) ethanolic extract to attenuate spontaneous typhlocolitis in mdr1a(-/-) mice. Methods: Vehicle (5% ethanol) or P. vulgaris ethanolic extract (2.4 mg/d) were administered daily by oral gavage to mdr1a(-/-) or wild type FVB(WT) mice from 6 wk of age up to 20 wk of age. Clinical signs of disease were noted by monitoring weight loss. Mice experiencing weight loss in excess of 15% were removed from the study. At the time mice were removed from the study, blood and colon tissue were collected for analyses that included histological evaluation of lesions, inflammatory cytokine levels, and myeloperoxidase activity. Results: Administration of P. vulgaris extracts to mdr1a(-/-) mice delayed onset of colitis and reduced severity of mucosal inflammation when compared to vehicle-treated mdr1a(-/-) mice. Oral administration of the P. vulgaris extract resulted in reduced (P < 0.05) serum levels of IL-10 (4.6 ± 2 vs 19.4 ± 4), CXCL9 (1319.0 ± 277 vs 3901.0 ± 858), and TNFα (9.9 ± 3 vs 14.8 ± 1) as well as reduced gene expression by more than two-fold for Ccl2, Ccl20, Cxcl1, Cxcl9, IL-1α, Mmp10, VCAM-1, ICAM, IL-2, and TNFα in the colonic mucosa of mdr1a(-/-) mice compared to vehicle-treated mdr1a(-/-) mice. Histologically, several microscopic parameters were reduced (P < 0.05) in P. vulgaris-treated mdr1a(-/-) mice, as was myeloperoxidase activity in the colon (2.49 ± 0.16 vs 3.36 ± 0.06, P < 0.05). The numbers of CD4(+) T cells (2031.9 ± 412.1 vs 5054.5 ± 809.5) and germinal center B cells (2749.6 ± 473.7 vs 4934.0 ± 645.9) observed in the cecal tonsils of P. vulgaris-treated mdr1a(-/-) were significantly reduced (P < 0.05) from vehicle-treated mdr1a(-/-) mice. Vehicle-treated mdr1a(-/-) mice were found to produce serum antibodies to antigens derived from members of the intestinal microbiota, indicative of severe colitis and a loss of adaptive tolerance to the members of the microbiota. These serum antibodies were greatly reduced or absent in P. vulgaris-treated mdr1a(-/-) mice. Conclusion: The anti-inflammatory activity of P. vulgaris ethanolic extract effectively attenuated the severity of intestinal inflammation in mdr1a(-/-) mice.
... For this study, 9 of these single WBFAs were selected because of their relation with the pathways of the inflammatory metabolism: palmitic acid, oleic acid, linoleic acid (LA), γ-linoleic acid, AA, α-linolenic acid, EPA, docosapentaenoic acid and DHA. 5,20,[25][26][27][28] In addition, n-3 highly unsaturated fatty acids (n-3 HUFA), highly unsaturated n-6 (n-6 HUFA) and the ratio between n-3 HUFA and n-3 HUFA+n-6 HUFA (×100 n-3 HUFA) were measured. The ratios calculated are, in some cases, indexes of WBFA conversion (from the precursor to the product, for example, LA/AA) or a simple ratio (n-3/n-6) with possible implications in the synthesis of eicosanoids. ...
Article
Background/objectives: Fatty acids are hypothesized to influence cardiovascular disease risk because of their effect on inflammation. The aim of this study is to assess the relationship between whole-blood fatty acids (WBFAs) and high-sensitivity C-reactive protein (hs-CRP) in European children. Subjects/methods: A total of 1401 subjects (697 boys and 704 girls) aged between 2 and 9 years from the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects in Children and infantS) study were measured in this cross-sectional analysis. The sample was divided into three categories of hs-CRP. Associations between WBFA and hs-CRP were assessed by logistic regression models adjusting for body mass index (BMI), country, age, breastfeeding, mother's education and hours of physical activity. Results: Linoleic acid (LA) (P=0.013, 95% confidence interval (CI): 0.822-0.977) and sum of n-6 WBFA (P=0.029, 95% CI: 0.866-0.992) concentrations were associated with lower concentrations of hs-CRP in boys. In girls, a high ratio of eicosapentaenoic acid (EPA)/arachidonic acid (AA) was associated (P=0.018, 95% CI: 0.892-0.989) with lower hs-CRP concentrations. In contrast, sum of blood n-6 highly unsaturated fatty acids (P=0.012, 95% CI: 1.031-1.284), AA (P=0.007, 95% CI: 1.053-1.395) and AA/LA ratio (P=0.005, 95% CI: 1.102-1.703) were associated (P<0.05) with higher concentrations of hs-CRP in girls. Conclusions: The n-6 WBFAs (sum of n-6 FA and LA) were associated with lower hs-CRP in boys and with higher hs-CRP in girls (AA, sum of n-6 highly unsaturated and AA/LA ratio). More studies are needed to identify the optimal levels of WBFAs to avoid low-grade inflammation in children considering the differences by sex and BMI.European Journal of Clinical Nutrition advance online publication, 13 January 2016; doi:10.1038/ejcn.2015.219.
... Palmitic Acid and Trained Immunity: Palmitic acid (PA) is a long-chain saturated fatty acid that is found in diets enriched in animal fats including meat, milk, and butter, (Carta, et al., 2017). Many groups have shown that PA can induce inflammation in macrophages and monocytes, (Napier et al., 2019, Korbecki, et al. 2019, Laine, et al., 2007, Tzeng, et al., 2019, Schwartz, et al., 2010. ...
... Some of the fatty acids that were elevated in LbrM (i.e., myristic and palmitic acids) may affect the inflammatory reaction, playing a key role in parasite tropism or exert pro-inflammatory activities. Others may affect protein anchoring to membranes (which is critical for the recognition and attachment of parasites to host cells) or signal transduction pathways [40][41][42][43]. ...
Article
Full-text available
Background: Leishmaniasis is a complex disease in which clinical outcome depends on factors such as parasite species, host genetics and immunity and vector species. In Brazil, Leishmania (Viannia) braziliensis is a major etiological agent of cutaneous (CL) and mucosal leishmaniasis (MCL), a disfiguring form of the disease, which occurs in ~10% of L. braziliensis-infected patients. Thus, clinical isolates from patients with CL and MCL may be a relevant source of information to uncover parasite factors contributing to pathogenesis. In this study, we investigated two pairs of L. (V.) braziliensis isolates from mucosal (LbrM) and cutaneous (LbrC) sites of the same patient to identify factors distinguishing parasites that migrate from those that remain at the primary site of infection. Methodology/principal findings: We observed no major genomic divergences among the clinical isolates by molecular karyotype and genomic sequencing. RT-PCR revealed that the isolates lacked Leishmania RNA virus (LRV). However, the isolates exhibited distinct in vivo pathogenesis in BALB/c mice; the LbrC isolates were more virulent than the LbrM isolates. Metabolomic analysis revealed significantly increased levels of 14 metabolites in LbrC parasites and 31 metabolites in LbrM parasites that were mainly related to inflammation and chemotaxis. A proteome comparative analysis revealed the overexpression of LbrPGF2S (prostaglandin f2-alpha synthase) and HSP70 in both LbrC isolates. Overexpression of LbrPGF2S in LbrC and LbrM promastigotes led to an increase in infected macrophages and the number of amastigotes per cell at 24-48 h post-infection (p.i.). Conclusions/significance: Despite sharing high similarity at the genome structure and ploidy levels, the parasites exhibited divergent expressed genomes. The proteome and metabolome results indicated differential profiles between the cutaneous and mucosal isolates, primarily related to inflammation and chemotaxis. BALB/c infection revealed that the cutaneous isolates were more virulent than the mucosal parasites. Furthermore, our data suggest that the LbrPGF2S protein is a candidate to contribute to parasite virulence profiles in the mammalian host.
... Slično je i ponašanje TNF-α koji pokazuje povišene vrednosti kod astmatičara, ali i kod gojaznih i posle unošenja hrane bogate mastima. Monociti periferne krvi sa refraktarnom astmom pokazuju povećanu ekspresiju TNF-α, TNFR1 i TNF-α konvertujućeg enzima 25 . TNF-α pokazuje efekte na glatke mišiće disajnih puteva. ...
... Cultured astrocytes take up exogenously added fatty acids (Bernoud et al., 1998;Morand et al., 1979), which suggest that astrocytes located near the BBB may take up and accumulate the excess fatty acids that are derived from the diet and deliver these fatty acids to neurons. Saturated free fatty acids, such as palmitic acid (PA) and lauric acid (LA), trigger some inflammatory markers in cultured macrophages (Laine et al., 2007) and modulate amyloid processing in neurons and astrocytes (Patil et al., 2006;Patil and Chan, 2005). Indeed, when cortical neurons are exposed to conditioned medium isolated from PA-treated astrocytes, the expression of BACE-1 is increased and, consequently, the levels of the C-terminal fragment of APP (C99) are elevated (Fig. 4). ...
Article
A growing body of research suggests that astrocytes play roles as contributors to the pathophysiology of Alzheimer's disease (AD). Several lines of evidence suggest that activated astrocytes produce and release proinflammatory molecules that may be critical for the generation of amyloid-β peptide (Aβ). However, accumulating evidence indicates that Aβ may activate astrocytes, which leads to an increase in cytokines that has been suggested to be a causative factor in the cognitive dysfunction of AD; thus, a vicious circle may be created. Intrinsic inflammatory mechanisms may provide a regulatory system that is capable of influencing the neuronal microenvironment that affects neuronal survival. In this article, we address the evidence surrounding the interactions of dysfunctional astrocytes with neighboring neurons that may initiate a cascade of events that culminates with neuronal injury and the expression of the hallmark lesions of AD. Comprehensive knowledge of the molecular mechanisms underlying the participation of astrocytes in neurodegeneration could aid the development of therapies to restore proper astrocyte function that can be used in AD patients to prevent or alleviate the progression of the disease in a more efficient and comprehensive manner.
... Two inflammatory markers, hsCRP and IL-6, had a strong positive association with stearic acid (C18:0), but not palmitic acid (C16:0). Generally, exposure to palmitic acid is associated with its proinflammatory effect on variety of cells [23,24]. It has also been previously reported that C18:0 from PBMC phospholipids was negatively correlated with IL-6 production after inflammatory stimulus [10]. ...
Article
Full-text available
Metabolic profiling of peripheral blood mononuclear cells (PBMC) could serve as a less invasive and more direct alternative to tissue biopsies or serum in metabolomic research. We conducted two exploratory independent studies in order to characterise PBMC's metabolomic profile following short-term vitamin D3 supplementation and to determine gender effects. In the first study, eight healthy males and females aged 40-65 y were randomly selected for profiling of PBMCs after receiving either 15 µg of vitamin D3 or placebo for four weeks. In the second study, twenty younger healthy males and females were studied. Cell metabolites were extracted and deproteinised using methanol/chloroform/water method and analysed by GC-MS. Higher vitamin D status had no effect on the fatty acid profile of PBMCs, but inflammatory biomarkers and adipokines correlated positively with stearic acid levels. In the second study, no gender-specific metabolites were identified. Valine, leucine and aspartic acid were identified as potential BMI-sensitive amino acids. Larger studies are needed to confirm the influence of BMI on these parameters. This work clearly demonstrates the utility of metabolomics profiling of PBMCs and paves the way for future applications of metabolomics in identifying metabolic profiles of blood cells as a measure for dietary intakes or physiological status.
... The increased plasma cytokines in obesity are in response to increased plasma microbial components and lipotoxicity. The presence of lipotoxic substances, including the saturated fatty acids, palmitic, stearic and lauric acid, [73][74][75][76] and microbial components 77,78 have the ability to activate toll-like receptors (TLR) which then initiate immune responses. ...
Article
Full-text available
Obesity was probably rare in ancient times, with the current increase starting in the Industrial Revolution of the eighteenth century, and becoming much more widespread from about 1950, so concurrent with the increased consumption of carbohydrates from cereals in the Green Revolution. However, dietary components such as oligosaccharides from plants including cereals may improve health following fermentation to shortchain carboxylic acids in the intestine by bacteria as part of the microbiome. Such nondigestible and fermentable components of diet, called prebiotics, have been part of the human diet since at least Palaeolithic times, and include components of the cereals domesticated in the Neolithic Revolution. If consumption of these cereals has now increased, why is obesity increasing? One reason could be lowered prebiotic intake combined with increased intake of simple sugars, thus changing the bacteria in the microbiome. Processing of food has played an important role in this change of diet composition. Since obesity is a lowgrade inflammation,changing the microbiome by increased consumption of simple carbohydrates and saturated fats may lead to obesity via increased systemic inflammation. Conversely, there is now reasonable evidence that increased dietary prebiotic intake decreases inflammation, improves glucose metabolism and decreases obesity. Would widespread increases in prebiotics in the modern diet, so mimicking Palaeolithic or Neolithic nutrition, decrease the incidence and morbidity of obesity in our communities?
... In vitro studies with murine and human cell lines have demonstrated that palmitate, an endogenous and dietary long-chain saturated fatty acid (SFA), can induce inflammation in adipocytes. 25 The SFA-induced adipose tissue inflammation (which is correlated to obesity-induced insulin resistance) involves indirect activation of Toll-like receptor 4 (a receptor that binds bacterial LPS) with subsequent NF-6B-dependent upregulation of proinflammatory gene ex-pression in macrophages and white adipose tissue. 26 Nevertheless, thorough histopathological evaluation showed that the general progression of the tissue response elicited by i.m. administration of water-insoluble PS was very similar to that of PPP-LAI injections ( Fig. 3; Supporting Information, Fig. S5), suggesting a negligible contribution of esterified or slowly released palmitate on the overall reaction. ...
Article
The present study aims at elucidating the intricate nature of the drug release and absorption following intramuscular (i.m.) injection of sustained-release prodrug nanocrystals/microcrystals. A paliperidone palmitate (PPP) long-acting suspension was characterized with regard to particle size (Dv,50 = 1.09 μm) and morphology prior to i.m. injection in rats. The local disposition was rigorously investigated by means of (immuno)histochemistry and transmission electron microscopy while the concurrent multiphasic pharmacokinetics was linked to the microanatomy. A transient (24 h) trauma-induced inflammation promptly evolved into a subclinical but chronic granulomatous inflammatory reaction initiated by the presence of solid material. The dense inflammatory envelope (CD68+ macrophages) led to particle agglomeration with subsequent drop in dissolution rate beyond 24 h postinjection. This was associated with a decrease in apparent paliperidone (PP) absorption (near-zero order) until 96 h and a delayed time of occurrence of observed maximum drug plasma concentration (168 h). The infiltrating macrophages phagocytosed large fractions of the depot, thereby influencing the (pro)drug release. Radial angiogenesis (CD31+) was observed throughout the inflammatory rim from 72 h onwards and presumably contributed to the sustained systemic PP concentrations by maintaining a sufficient absorptive capacity. No solid-state transitions of the retrieved formulation were recorded with X-ray diffraction analysis. In summary, the initial formulation-driven prodrug (PPP) dissolution and drug (PP) absorption were followed by a complex phase determined by the relative contribution of formulation factors and dynamic physiological variables. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
... It is well known the effects of hyperglycemia and hyperlipidemia on peripheral blood mononuclear cells (PBMNCs) by activation of NADPH oxidase system leading to reactive oxygen species production, TLR expression, enhancing NF-kappaB activity, and inducing proinflammatory cytokines, chemokines, and circulating adhesion molecules secretion [8,21,[31][32][33][34][35][36][37][38][39][40][41]. ...
Article
Full-text available
We examined nitric oxide (NO), IL-6, and TNF- α secretion from cultured palmitate-stimulated PBMNCs or in the plasma from type 2 diabetes mellitus (T2MD) patients or nondiabetic (ND) controls. Free fatty acids (FFA) have been suggested to induce chronic low-grade inflammation, activate the innate immune system, and cause deleterious effects on vascular cells and other tissues through inflammatory processes. The levels of NO, IL-6, TNF- α , and MDA were higher in supernatant of palmitate stimulated blood cells (PBMNC) or from plasma from patients. The results obtained in the present study demonstrated that hyperglycemia in diabetes exacerbates in vitro inflammatory responses in PBMNCs stimulated with high levels of SFA (palmitate). These results suggest that hyperglycemia primes PBMNCs for NO, IL-6, and TNF-alpha secretion under in vitro FFA stimulation are associated with the secretion of inflammatory biomarkers in diabetes. A combined therapy targeting signaling pathways activated by hyperglycemia in conjunction with simultaneous control of hyperglycemia and hypertriglyceridemia would be suggested for controlling the progress of diabetic complications.
... FFA has been demonstrated to trigger the inflammatory response in macrophages (15,24,32) and is considered an important adipocyte-derived mediator of inflammation in macrophages (29). Thus we evaluated the response of macrophages to FFA in the context of CKD. ...
Article
White adipose tissue plays an important role in the development of metabolic disturbance which is a common feature in patients with chronic kidney disease (CKD). The effect of CKD on white adipose tissue remains poorly appreciated. Here we evaluated the inflammatory potential of visceral white adipose tissue in a rat model of CKD. The results showed production of pro-inflammatory cytokines and infiltration of macrophage in the tissue were significantly increased in CKD rats than sham rats. Moreover, the primary adipocytes and stromal vascular fraction under the condition of CKD could trigger the inflammatory response in each other. Free fatty acid induced robust inflammatory response in ex vivo peritoneal-derived macrophages from CKD rats, which was associated with reduced activity of silent information regulator T1 (SIRT1). Improvement of SIRT1 activity by an activator could alleviate free fatty acid-induced inflammatory response in the macrophages and inflammation in the white adipose tissue. Moreover, oxidative stress occurred in the tissue and linked with the reduced activity of SIRT1 in macrophages and enhanced release of free fatty acid in the tissue. We thus identified CKD as a risk factor for chronic inflammation in white adipose tissue. These observations might open up new therapeutic strategies for metabolic disturbance in CKD via the modulation of adipose tissue-related pathways.
... Plasma content of free fatty acids was unaffected ( Fig. 6A) but total palmitic acid and eicosapentaenoic acid (EPA) were found to be significantly increased in LERKO mice (Fig. 6B). It is known that the saturated palmitic acid activates microglia and macrophages 45,46 through stimulation of TLR4 receptor 45 , thus suggesting its involvement in microglia activation in LERKO mice and in N9 cells in vitro. ...
Article
Full-text available
Recent work revealed the major role played by liver Estrogen Receptor α (ERα) in the regulation of metabolic and reproductive functions. By using mutant mice with liver-specific ablation of Erα, we here demonstrate that the hepatic ERα is essential for the modulation of the activity of Agouti Related Protein (AgRP) neurons in relation to the reproductive cycle and diet. Our results suggest that the alterations of hepatic lipid metabolism due to the lack of liver ERα activity are responsible for a neuroinflammatory status that induces refractoriness of AgRP neurons to reproductive and dietary stimuli. The study therefore points to the liver ERα as a necessary sensor for the coordination of systemic energy metabolism and reproductive functions.
... Excess fat consumption can induce a lipotoxic state, involving activation of various inflammatory pathways [3]. As early as one hour after consumption of a high fat meal, nuclear factor-kB, a key regulator of fat-induced inflammation [4,5], is activated [6,7], likely due to the activation of cell surface receptors by free fatty acids [8][9][10]. This leads to increased expression of pro-inflammatory mediators, including interleukin-6 (IL-6), tumour necrosis α (TNF-α) and interleukin-8 (IL-8) [10,11]. ...
Article
Full-text available
One of the limitations for ranking foods and meals for healthiness on the basis of the glycaemic index (GI) is that the GI is subject to manipulation by addition of fat. Postprandial lipemia, defined as a rise in circulating triglyceride containing lipoproteins following consumption of a meal, has been recognised as a risk factor for the development of cardiovascular disease and other chronic diseases. Many non-modifiable factors (pathological conditions, genetic background, age, sex and menopausal status) and life-style factors (physical activity, smoking, alcohol and medication use, dietary choices) may modulate postprandial lipemia. The structure and the composition of a food or a meal consumed also plays an important role in the rate of postprandial appearance and clearance of triglycerides in the blood. However, a major difficulty in grading foods, meals and diets according to their potential to elevate postprandial triglyceride levels has been the lack of a standardised marker that takes into consideration both the general characteristics of the food and the food’s fat composition and quantity. The release rate of lipids from the food matrix during digestion also has an important role in determining the postprandial lipemic effects of a food product. This article reviews the factors that have been shown to influence postprandial lipemia with a view to develop a novel index for ranking foods according to their healthiness. This index should take into consideration not only the glycaemic but also lipemic responses.
... However, unsaturated fatty acids fail to activate NLRP3-PYCARD-inflammasomes [118]. PA also increases expressions of inflammatory genes such as TNF and IL-6 [119,120] in the macrophages via TLR4-dependent and NFκBdependent mechanisms [121][122][123][124]. In other cell types such as astrocytes, PA-but not unsaturated fatty acids-triggers release of TNFα and IL-6 from astrocytes in a TLR-4-dependent manner, suggesting that high levels of circulating PA cause reactive gliosis and brain inflammation, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome [125]. ...
Article
Full-text available
Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many diseases at the molecular level. In this review, we focus on its regulatory roles in the development of five pathological conditions, namely, metabolic syndrome, cardiovascular diseases, cancer, neurodegenerative diseases, and inflammation. We summarize the clinical and epidemiological studies; and also the mechanistic studies which have identified the molecular targets for PA in these pathological conditions. Activation or inactivation of these molecular targets by PA controls disease development. Therefore, identifying the specific targets and signaling pathways that are regulated by PA can give us a better understanding of how these diseases develop for the design of effective targeted therapeutics.
... The limit of statistical significance was set at p<0.05. The group mean values with different letters (a, b, c) Laine et al., 2007), the results of this study and data from the literature show that PO has anti-inflammatory properties due to its high tocotrienol content. ...
Article
Full-text available
Palm olein (PO) and olive oil (OO) are widely consumed in the world. PO is considered harmful to health, whereas OO is considered healthy. The aim of the study was to compare the effects of consumption of these oils on antioxidant status and inflammation in rats. This was an experimental study in male wistar rats fed a diet containing 30% of each oil. Rats had free access to food and water. After being fed for 12 weeks, animals were sacrificed and liver and aortic blood were collected. Plasma was used for the determination of interleukin-6 (IL-6) and oxidative stress parameters (Superoxide dismutase -SOD; Gluthation peroxidase - GPx; Thiobarbituric acid reactive substances - TBARS; Thiol groups and isoprostane). The inflammation and oxidative stress status as well as the expression of several genes/proteins were also analyzed in liver homogenate. No significant differences were observed between PO and OO in plasma and liver levels of the studied inflammation and oxidative stress parameters. This study showed that the consumption of PO induces an antioxidant status superimposable to that of OO. Key words : Palm olein - Olive oil - Oxidative stress - Inflammation - High fat diet
... Co-treatment with the omega-3 FA DHA reversed the effect of saturated FAs in a PPARγ-dependent manner [61]. Similarly, treatment of macrophages with palmitic acid stimulated MCP-1 and IL-8 expression [62]. Palmitic acid treatment increased macrophage production of IL-8 and CXCL1 [63]. ...
Article
Full-text available
Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent 19 partly on their state of activation and partly on the availability of various energy yielding and bio-20 synthetic substrates (fatty acids, glucose and amino acids). These substrates are essential to fuel-21 based metabolic reprogramming that is supports optimal immune function, including the inflam-22 matory response. In this review, we will focus on metabolism in macrophages and lymphocytes and 23 discuss the role of fatty acids in governing the phenotype, activation and functional status of these 24 important cells. We summarize the current understanding of the pathways of fatty acid metabolism 25 and related mechanisms of action as well as explore possible new perspectives in this exciting area 26 of research. 27<br/
... For example, according to a report by Klein-Platat et al. [23], overweight adolescents display higher levels of circulating PA compared to their lean counterparts, with the polyunsaturated fatty acid: saturated fatty acid ratio being inversely associated with interleukin-6 (IL-6), thus further supporting the proinflammatory role of PA. PA has also been reported to activate systemic inflammatory signalling pathways and induce the secretion of pro-inflammatory cytokines in cultured peripheral immune cells, such as macrophages and monocytes [24][25][26]. While the effects of SFA on neuroinflammation remain to be fully characterized, there is compelling evidence that SFA are able to alter CNS physiology [12,27,28]. ...
Article
Full-text available
Neuroinflammation has been implicated in the pathogenesis of neurodegeneration and is now accepted as a common molecular feature underpinning neuronal damage and death. Palmitic acid (PA) may represent one of the links between diet and neuroinflammation. The aims of this study were to assess whether PA induced toxicity in neuronal cells by modulating microglial inflammatory responses and/or by directly targeting neurons. We also determined the potential of oleic acid (OA), a monounsaturated fatty acid, to counteract inflammation and promote neuroprotection. We measured the ability of PA to induce the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the induction of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways, as well as the phosphorylation of c-Jun, and the expression of inducible nitric oxide synthase (iNOS). Finally, to determine whether PA exerted an indirect neurotoxic effect on neuronal cells, we employed a microglia-neuron co-culture paradigm where microglial cells communicate with neuronal cells in a paracrine fashion. Herein, we demonstrate that PA induces the activation of the NF-κB signalling pathway and c-Jun phosphorylation in N9 microglia cells, in the absence of increased cytokine secretion. Moreover, our data illustrate that PA exerts an indirect as well as a direct neurotoxic role on neuronal PC12 cells and these effects are partially prevented by OA. These results are important to establish that PA interferes with neuronal homeostasis and suggest that dietary PA, when consumed in excess, may induce neuroinflammation and possibly concurs in the development of neurodegeneration.
... NF-κβ signaling cascade might be triggered by a variety of pathogenic factors, including TNF-α, IL-1, and reactive oxygen species (ROSs). 5 When LPS binds to toll-like receptors (TLRs), it starts an inflammatory signaling cascade that includes mitogen-activated protein kinases (MAPKs) as well as NF-κB, 6 as a result of which the expression of proinflammatory genes is increased. LPS also enforces the production of ROS through stimulating TLR4-NADPH oxidases-ROS-poly ADP-ribose polymerase (PARP) pathway. ...
Article
It is indicated that malvidin has anti-inflammatory and antioxidant effects on various cells, although the function of malvidin in preventing inflammatory reactions caused by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs) is still not known. The objective of this study was to examine the impact of malvidin on inflammatory responses and oxidative stress in PBMCs as caused by LPS. The present findings showed that LPS significantly increased the expression of IL-6, TNF-α, IL-1β, and COX-2 mRNA and protein release from PBMCs 22 hr after treatments. It was also revealed that increased levels in cytokine expression coincided with increased phosphorylation of JNK, P65-NF-κB, and IKKα/IKKβ. Also, the expression of IL-6, TNF-α, IL-1β, and COX-2 mRNA induced by LPS as well as secretion of protein in PBMC has been significantly decreased by pretreatment of malvidin. Importantly, pretreatment of the cells with malvidin completely abrogated the phosphorylation of P65-NF-κB, JNK, and IKKα/IKKβ in LPS treated cells. Malvidin protection against LPS-induced inflammation was coupled with a decline in the levels of nitric oxide metabolite and malondialdehyde, along with an increase in the ferric reducing antioxidant power, total thiol activity, and also superoxide dismutase and glutathione peroxidase activity. In accordance with this finding, malvidin may represent a promising therapeutic agent for the prevention of inflammation in PBMCs.
... Our study also demonstrated that the fatty acid components, present in the total lipids, were themselves able to regulate the inflammatory response in a similar fashion to TL. This observation is important as the principal fatty acids present were predominantly saturated, in particular, palmitic acid-that has previously been identified as being pro-inflammatory [43]. Given that, we attributed the potent anti-inflammatory actions of TL to the presence of a mixture of saturated and unsaturated FAs. ...
Article
Background: Camel milk is widely used for its reported anti-diabetic and health promoting effects. Lipids derived from the milk have also been shown to exhibit potent anti-inflammatory effects. The mechanism through which these lipids and constituent fatty acids exert these effects remains elusive. The aim of this study was to investigate the effect of camel milk on glycated protein-mediated macrophage inflammation. Methods: To determine the effect of Total Lipids (TL) and Total Fatty Acids (TFA) derived from camel milk on an in vitro model of diabetic inflammation, differentiated THP-1 (dTHP-1) cells stimulated with glycated serum albumin (gBSA) was employed. Cells were pre-treated with TL or TFA before challenging cells with gBSA. Results: Gas Chromatography-Mass Spectrometry (GC-MS) analysis found that TL was 96% triacylglycerol (TAG) while the TFA comprised 65% saturated and 35% unsaturated fatty acids. Both TL and TFA significantly (p<0.05) decreased gBSA-induced secretion of pro-inflammatory cytokines (Tumour necrosis factor-(TNF)-α, Interleukin-(IL)-1β/18). TL also demonstrated the ability to regulate the expression of p50/p65 sub-units of Nuclear Factor-kappa B (NF-κB), while concomitantly increasing the expression of regulatory cytokines IL-10, IL-1 Receptor Antagonist (IL-1Ra) and Cluster of Differentiation 163 (CD163)-shifting cells towards an M2 macrophage phenotype. Additionally, we found that TL significantly regulated the expression of Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome subunit and its regulator; Ten-Eleven Translocation-2 (TET-2). Conclusion: This paper demonstrates the ability of camel milk lipids to regulate gBSA-induced macrophage inflammation in vitro, by modulating the expression of key inflammatory regulators such NF-kB and NLRP3 inflammasome subunit.
... Moreover, previous studies have demonstrated that excessive circulating levels of FFAs are released from ectopic fat deposits, which activate TNF-α, protein kinase C, c-Jun NH2-terminal kinase, JNK1, and IL-6 expression (28)(29)(30) in the state of obesity. The concentrations of FFAs in vivo range from 0.1 to 1 mM (31,32). Therefore, we chose an FFA concentration of 0.5 mM for our studies to reflect a conservative estimate of the in vivo conditions. ...
Article
Free fatty acids (FFAs) increase in visceral fat and are inferred to be one of the underlying inducers of adipose tissue inflammation. In our previous study, it was demonstrated that ginsenoside Rb1 stimulates endothelial nitric oxide synthase (eNOS) and Sirtuin 1 to protect against endothelial cell senescence. In the present study, 3T3‑L1 adipocytes were exposed to 0.5 mM FFAs with or without Rb1 (10‑40 µM). Monocyte chemotactic protein‑1 (MCP‑1) and interleukin‑6 (IL‑6) secretion was measured using ELISA. Tumor necrosis factor‑α (TNF‑α) expression and nuclear factor‑κB (NF‑κB) p65 phosphorylation were detected using western blot analysis. Oxidative stress was determined via measuring intracellular reactive oxygen species (ROS) and nitric oxide (NO) production. The results demonstrated that MCP‑1 and IL‑6 secretion, as well as TNF‑α expression, were significantly increased following FFA treatment, which was attenuated by Rb1 in a dose‑dependent manner. Furthermore, Rb1 attenuated FFA‑induced NF‑κB phosphorylation, suggesting that the inhibitory effect of Rb1 on inflammatory cytokines was partially mediated through blockade of NF‑κB phosphorylation. Further experiments demonstrated that Rb1 ameliorated FFA‑induced ROS generation and NO reduction through upregulation of superoxide dismutase 2 and eNOS expression. Taken together, these results demonstrate proinflammatory and pro‑oxidant effects of FFA on 3T3‑L1 adipocytes, which are effectively ameliorated by Rb1. Suppression of inflammatory responses and oxidative stress may be a novel mechanism for attenuating the effect of Rb1 on adipocyte dysfunction.
... Our study also demonstrated that the fatty acid components, present in the total lipids, were themselves able to regulate the inflammatory response in a similar fashion to TL. This observation is important as the principal fatty acids present were predominantly saturated, in particular, palmitic acid-that has previously been identified as being pro-inflammatory [43]. Given that, we attributed the potent anti-inflammatory actions of TL to the presence of a mixture of saturated and unsaturated FAs. ...
Article
Full-text available
Background: Camel milk is widely used for its reported anti-diabetic and health promoting effects. Lipids derived from the milk have also been shown to exhibit potent anti-inflammatory effects. The mechanism through which these lipids and constituent fatty acids exert these effects remains elusive. The aim of this study was to investigate the effect of camel milk on glycated protein-mediated macrophage inflammation. Methods: To determine the effect of Total Lipids (TL) and Total Fatty Acids (TFA) derived from camel milk on an in vitro model of diabetic inflammation, differentiated THP-1 (dTHP-1) cells stimulated with glycated serum albumin (gBSA) was employed. Cells were pre-treated with TL or TFA before challenging cells with gBSA. Results: Gas Chromatography-Mass Spectrometry (GC-MS) analysis found that TL was 96% triacylglycerol (TAG) while the TFA comprised 65% saturated and 35% unsaturated fatty acids. Both TL and TFA significantly (p
... Our study also demonstrated that the fatty acid components, present in the total lipids, were themselves able to regulate the inflammatory response in a similar fashion to TL. This observation is important as the principal fatty acids present were predominantly saturated, in particular, palmitic acid-that has previously been identified as being pro-inflammatory [43]. Given that, we attributed the potent anti-inflammatory actions of TL to the presence of a mixture of saturated and unsaturated FAs. ...
Book
Background: Camel milk is widely used for its reported anti-diabetic and health promoting effects. Lipids derived from the milk have also been shown to exhibit potent anti-inflammatory effects. The mechanism through which these lipids and constituent fatty acids exert these effects remains elusive. The aim of this study was to investigate the effect of camel milk on glycated protein-mediated macrophage inflammation. Methods: To determine the effect of Total Lipids (TL) and Total Fatty Acids (TFA) derived from camel milk on an in vitro model of diabetic inflammation, differentiated THP-1 (dTHP-1) cells stimulated with glycated serum albumin (gBSA) was employed. Cells were pre-treated with TL or TFA before challenging cells with gBSA. Results: Gas Chromatography-Mass Spectrometry (GC-MS) analysis found that TL was 96% triacylglycerol (TAG) while the TFA comprised 65% saturated and 35% unsaturated fatty acids. Both TL and TFA significantly (p<0.05) decreased gBSA-induced secretion of pro-inflammatory cytokines (Tumour necrosis factor-(TNF)-α, Interleukin-(IL)-1β/18). TL also demonstrated the ability to regulate the expression of p50/p65 sub-units of Nuclear Factor-kappa B (NF-κB), while concomitantly increasing the expression of regulatory cytokines IL-10, IL-1 Receptor Antagonist (IL-1Ra) and Cluster of Differentiation 163 (CD163)-shifting cells towards an M2 macrophage phenotype. Additionally, we found that TL significantly regulated the expression of Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome subunit and its regulator; Ten-Eleven Translocation-2 (TET-2). Conclusion: This paper demonstrates the ability of camel milk lipids to regulate gBSA-induced macrophage inflammation in vitro, by modulating the expression of key inflammatory regulators such NF-kB and NLRP3 inflammasome subunit.
... Levels of IL-8, MIG, and IP-10 have been clearly demonstrated to be increased in relation to obesity (Duarte et al., 2015;Laine et al., 2007;Zhang et al., 2016). Serum levels of IL-8/CXCL8 are significantly higher in subjects with obesity compared to healthy controls (Borges et al., 2018). ...
Article
Full-text available
Obesity is a chronic disorder that is associated with body mass index (BMI) of greater or equal to 30 kg/m ² . The prevalence of obesity in the Kingdom of Saudi Arabia (KSA) is increasing at an alarming rate and is expected to reach 41% in men and up to 78% in women by 2022. Since chemokines are associated with involuntary weight loss, the objective of this study was to elucidate their association with BMI among Saudis. A questionnaire was used to collect information about diet, health conditions, and demographics from 15 men and 16 women who participated in the study. BMI was calculated based on clinical measurements and participants were classified according to their BMI category as: normal, underweight, overweight, or obese. Serum samples were collected for a multiplex assay using the Human Chemokine Magnetic 30-plex panel. The serum concentration of either the monokine induced by gamma interferon (MIG) or the CXC-motif chemokine ligand 9 (CXCL-9) was significantly increased in obese men (P = 0.0194) and women (P = 0.043) as compared to underweight men and women, respectively. However, the serum levels of other chemokines were not significantly different among the groups. We found that MIG levels are differentially regulated in serum, based on individuals’ BMI.
... Malgré sa richesse en acides gras saturés, notamment en acide palmitique, qui est considéré comme pro-inflammatoire car activateur de la voie NF-kB (Ajuwon et al., 2005;Laine et al., 2007), les résultats de cette étude et les données de la littérature montrent que l'huile de palme aurait plutôt des propriétés anti-inflammatoires dues à sa forte teneur en tocotriénols. ...
Thesis
L’huile de palme est l’huile végétale la plus consommée au monde. Du fait de sa teneur élevée en acides gras saturés (AGS), notamment en acide palmitique, cette huile est considérée par certains auteurs comme potentiellement nocive pour la santé. Cette étude avait pour objectif de comparer les effets de l’huile de palme (rouge ou oléine), à l’huile d’olive (réputée bonne pour la santé) et aux saindoux (riche en AGS), sur la santé. Pour réaliser cette étude, 40 rats mâles Wistar ont été répartis en 5 groupes de 8 rats chacun : 1 groupe contrôle et 4 groupes nourris par des régimes obésogènes contenant respectivement de l’huile de palme rouge, de l’oléine de palme, de l’huile d’olive ou du saindoux. Après 12 semaines de régime, les rats ont été sacrifiés et les tissus prélevés. Les examens réalisés sur les tissus ont montré que l’huile de palme (rouge ou oléine) induit un statut antioxydant et un profil lipidique superposables à ceux de l’huile d’olive. Tous les régimes obésogènes ont favorisé la prise de poids, l’altération de la fonction mitochondriale et la perturbation du métabolisme glucidique par l’induction d’une insulino-résistance. Il ressort de cette étude que l’huile d’olive est plus délétère pour le foie que l’huile de palme (rouge ou oléine) et le saindoux. Hormis l’huile de palme rouge, l’oléine de palme, l’huile d’olive et le saindoux influencent négativement les tissus adipeux. Les études menées sur l’aorte ont montré que les effets vasculaires de l’huile de palme sont moins délétères pour l’aorte que le saindoux et l’huile d’olive.Les résultats de cette étude indiquent que globalement, l’huile de palme (rouge ou oléine) n’a pas d’effets délétères supérieurs à ceux de l’huile d’olive concernant les organes qui ont été étudiés
Article
Objectives: Type 2 diabetes (T2D)-associated cognitive impairment is highly prevalent especially among the geriatric population. Here, we investigate the role of exercise in T2D-associated cognitive decline in rats. Methods: T2D was induced using high-fat diet (15 days) followed by low-dose STZ (25mg/kg). The T2D animals were subjected to aerobic exercise on running wheel for 6 weeks. Effect of aerobic exercise on cognitive performance of T2D animals was measured using step-down and transfer latency tests. This was followed by the measurement of reduced glutathione levels in hippocampal homogenates. We also measured hippocampal AchE activity and levels of neuroinflammatory markers such as IL-1 β, TNF-α and MCP-1. Morphology and density of hippocampal neurons were also determined by histopathological studies. Results: Exercise led to the following changes in T2D animals. It led to decrease in fasting blood glucose level (<250 mg/kg) and HbA1c (8.5 ± 0.23) compared to diabetic (11.73 ± 0.14) animals and improved insulin resistance. There was an increase in step-down latency (p < 0.001) and a decrease in transfer latency (p < 0.01) suggesting improved cognitive function. A significant increase in GSH levels (1.828 ± 0.024) compared to diabetic group (1.52 ± 0.03; p < 0.001) and decrease in AchE activity (1.4 ± 0.05) compared to diabetic group (1.65 ± 0.03; p < 0.05) were also observed. It reduced the levels of neuroinflammatory markers such as IL-1β, TNF-α and MCP-1 (p < 0.01). Hippocampal sections showed higher CA1 and CA3 neuronal density (p < 0.001) than T2D group. Conclusion: We may conclude that aerobic exercise could partially reverse diabetes-associated cognitive decline by reducing oxidative stress and inflammatory milieu in T2D animal brain.
Article
Based primarily on cell culture results, saturated fatty acids (SFAs) are proposed to promote inflammation and contribute to metabolic dysfunction through toll-like receptor activation. Studies are often complicated by a requirement for carriers (e.g. BSA) or solvents (e.g. ethanol) to increase SFA solubility. To ascertain if these factors influence interpretations of SFA-associated inflammation activity, we measured responses of RAW264.7 monocyte/macrophages and C2C12 myotubes to various BSA, ethanol and cyclodextrin (alternative FA carrier) conditions. Fatty acid free low-endotoxin BSA preparations (0.33% to 2% wt/vol) activated, whereas 0.5-1.0% ethanol inhibited, RAW264.7 TNF- release. Ethanol modestly increased IL-6 secretion in C2C12 myotubes. Cyclodextrins (0.3 - 6.0 mM) were tested as alternative carriers of palmitate, but their usefulness was limited due to toxicity and solubility issues. Using a lower-inflammation BSA source and no ethanol, ~24 hr sodium palmitate treatment (up to 600 µM) failed to trigger RAW264.7 TNF- release, and in fact significantly dampened BSA-induced inflammation by >50%. In C2C12 myotubes, only high palmitate concentrations (500-600 µM) elicited IL-6 secretion (> 2.5-fold increase). Acute palmitate (200 or 500 µM) treatment did not activate MAP-kinase pathways above that of fresh BSA-containing media alone in either cell type. These results highlight the importance of experimental conditions in studies exploring SFA inflammation effects. The limited (or even anti-inflammatory) effects of palmitate that we observed indicate that immunomodulatory effects of SFAs are context-specific. Thus, caution is needed when interpreting the literature related to putative pro-inflammatory effects of SFA.
Article
Résumé Cette synthèse fait le point sur la relation entre les apports en acides gras saturés (AGS) et le risque cardio-métabolique. Après un bref rappel biochimique, une petite note historique montre les bases du dogme de leur effet délétère. Celles-ci reposent essentiellement sur des études écologiques et sur le lien entre AGS et élévation du cholestérol. Or, les preuves de l’absence de lien entre l’apport en AGS et le risque cardio-métabolique s’accumulent depuis des années. Nous passons en revue les études prospectives, les études de substitution, les études de prévention primaire et secondaire, qui toutes confirment que les AGS dans leur ensemble n’ont pas d’effet négatif sur ce risque. En revanche, un apport suffisant en acides gras polyinsaturés oméga-6 (mais non excessif) et oméga-3 est souhaitable. Nous évoquons brièvement les effets des AGS sur différents marqueurs et facteurs du risque cardio-métabolique. Au total, il apparaît que la source des AGS importe, et pourrait rendre compte de l’erreur qui a été faite. Enfin, l’équilibre global de tous les acides gras, et donc leur diversité, doit être considéré.
Article
Obesity is a chronic low-grade inflammatory condition, with increased inflammatory mediators in the circulation and adipose tissue. Following up obese subjects before and after bariatric surgery, we observed a biphasic regulation of pro-inflammatory factors in circulation, showing drastic decreases at month 3 post-surgery followed by a rebound and stabilization after 1 year. Patient's nutritional status was a major determinant of this unexpected profile. In obese subjects, we found enrichment in "non-classical" CD14dimCD16+ circulating monocytes that was reduced after bariatric surgery. The pathogenicity of this particular subset in relation with low-grade inflammation remains to be established. Although obese adipose tissue is a site of immune cell infiltration in obesity, little is known about cross-talk between these cell types. We show that adipose tissue macrophages secrete IL-1β through NLRP3 inflammasome activation. This process was down-regulated by weight loss but overactivated in type 2 diabetic (T2D) patients. We also showed that the adipose tissue of obese T2D subjects is enriched in IL-17+IFN-β+ double producer lymphocytes. In primary cell co-culture experiments, adipose tissue macrophage-derived IL-1β enhanced IL-17 production by adipose tissue lymphocytes, while IL-17 reciprocally induced IL-1β secretion. T2D might exacerbate this cross-talk, as suggested by overexpression of each cytokine cognate receptor on their respective target cell. This identified IL-1β and IL-17 as two key cytokines mediating a new inflammatory cross-talk between adipose tissue macrophages and lymphocytes that might contribute to the deterioration of glycemic status in human obesity
Article
Background We try to explore whether long‐term consumption of two healthy dietary patterns (low‐fat (LF) diet or Mediterranean diet (MedDiet)) interact with the apolipoprotein E (APOE) single nucleotide polymorphisms (SNPs: rs439401, rs440446 and rs7412) modulating postprandial hypertriglyceridemia (ppHTG) in coronary heart disease (CHD) patients. Methods and results We selected patients from the CORDIOPREV study with genotyping and who underwent an oral fat load test (FLT) at baseline and after three years follow up (n = 506). After three years of follow‐up, we found a gene‐diet interaction between the APOE rs439401 SNP and MedDiet. Specifically, T‐allele carriers in the MedDiet group, showed a more significant decrease in postprandial triglycerides (TG: p = 0.03) and large triacylglycerol‐rich lipoproteins (TRLs)‐TG (large TRLs‐TG; p = 0.01) compared with CC subjects. Consistently, the area under the curve of TG (AUC‐TG; p‐interaction = 0.03) and AUC‐large TRLs‐TG (p‐interaction = 0.02) were significantly lower in T‐allele carriers compared with CC subjects. Conclusions The long‐term consumption of a MedDiet modulates ppHTG through APOE genetic variants in CHD patients. This gene‐diet interaction may contribute to a more precise dietary advice in CHD patients. This article is protected by copyright. All rights reserved.
Article
Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non‐Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre‐diagnosis red blood cell (RBC) specimens in the Nurses' Health Study (NHS) and Health Professionals Follow‐up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T‐NHL), B cell NHL (B‐NHL) and three individual B‐NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B‐NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0, and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T‐NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B‐NHLs other than CLL/SLL and for VLCSFA and MUFA with T‐NHL suggest an influence of fatty acid metabolism on lymphomagenesis. This article is protected by copyright. All rights reserved.
Article
Non-esterified fatty acids (NEFAs) are important induction factors of inflammatory responses in some metabolic diseases. High plasma levels of NEFAs and oxidative stress exist in the dairy cows with ketosis. The aim of this study was to investigate whether high levels of NEFAs can induce inflammatory response and the specific molecular mechanism in the hepatocytes of dairy cow. In vitro, primary cultured bovine hepatocytes were treated with different concentrations of NEFAs, PDTC (an NF-κB inhibitor) and NAC (an antioxidant). NEFAs significantly activated NF-κB pathway. Activated NF-κB upregulated the release of pro-inflammatory cytokines, thereby inducing inflammatory response in bovine hepatocytes. When PDTC was added, activation of NF-κB-mediated inflammatory response induced by NEFAs was inhibited. NEFAs treatment results in the overproduction of the markers of oxidative stress, reactive oxygen species (ROS) and malondialdehyde (MDA), which were ameliorated by NAC treatment. These increased ROS and MDA were caused by decreasing activity of antioxidant system, including glutathione peroxidase, superoxide dismutase and catalase, in bovine hepatocytes treated with NEFAs. NAC also ameliorated NEFAs-mediated NF-κB activation and the release of pro-inflammatory cytokines. These results indicate that high concentrations of NEFAs can induce cattle hepatocytes inflammatory response through activating the oxidative stress-mediated NF-κB signaling pathway.
Article
Sciatic nerve injury affects quality of life. Many immune cells and inflammatory cytokines have been reported to be involved in sciatic nerve injury, but little is known about the ligands and receptors that trigger inflammatory responses. By using a modified sciatic nerve clamp injury method, we found that the recruitment of Schwann cells and the inflammatory response were enhanced after sciatic nerve injury. Toll‐like receptor 4 (TLR4), one of the major members of the TLR family, is highly expressed in Schwann cells. Under certain conditions, myeloid differentiation protein 2 (MD2) binds to TLR4 on the membrane and plays important roles in the inflammatory response. The reductions in the recruitment of Schwann cells and the inflammatory response induced by the blockade of TLR4 or MD2 suggest that TLR4 and MD2 are involved in sciatic nerve injury. What are the endogenous signals that activate the inflammatory response? A large number of free saturated fatty acids (SFAs) are released from Schwann cells, adipocytes and the blood after sciatic nerve injury. Liang et al reported that Schwann cells can be stimulated by palmitic acid (PA). Here, we found that the expression and secretion of TNF‐α and IL‐6 were enhanced by PA treatment. Moreover, PA activated TLR4 signalling pathway‐related proteins and stimulated a strong association between TLR4 and MD2. Blocking TLR4 or MD2 reversed the PA‐induced inflammatory response and TLR4 downstream signalling pathway. Thus, we speculated that SFAs act as endogenous ligands that activate TLR4/MD2, thus triggering Schwann cell inflammation during sciatic nerve injury.
Article
Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disease. A wide range of techniques have been proposed to facilitate early diagnosis of AD, including biomarkers from the cerebrospinal fluid and blood. Although phosphorylated tau and amyloid beta are amongst the most promising biomarkers of AD, other peripheral biomarkers have been identified and in this review we synthesize the current knowledge on circulating fatty acids. Fatty acids are involved in different biological process including neurotransmission and inflammation. Interestingly, some fatty acids appear to be modulated during disease progression, including long chain saturated fatty acids, and polyunsaturated fatty acids, such as docosahexaenoic acid . However, discrepant results have been reported in the literature and there is the need for further validation and method standardization. Nonetheless, our literature review suggests that fatty acid analyses could potentially provide a valuable source of data to further inform the pathology and progression of AD.
Article
Neurodegenerative diseases have been found to be closely related to common mechanisms such as protein aggregation, neural oxidative stress, neuroinflammation, mitochondrial dysfunction, and gut microbiota dysbiosis. Although there are some drugs that can temporarily reduce symptoms, there is no cure for these diseases. Therefore, the discovery of molecules that can halt the pathology of these diseases is urgently needed in the present time. Fatty acids show positive effects on the pathology of neurodegenerative diseases, depending on the degree of unsaturation and the shortness of the hydrocarbon chain. Understanding the effects of different structures of fatty acids on the underlying mechanisms of neurodegenerative diseases and the balance of gut microbiota can produce positive implications for the development of future treatments. The present review focuses on the role of different fatty acid s on underlying mechanisms of neurodegenerative diseases, gut microbiota balance, and gut‐brain axis. This article is protected by copyright. All rights reserved
Article
Full-text available
Lipids as one of the main energy sources for cells make plasma membrane structure. About the brain, the only energy fuel is a glucose which makes wide various signaling pathways in the neurons. Most functions for lipids in the brain are narrowed to structural purposes such as myelin sheath. By increasing the rate of obesity and diabetes in the industrialized countries, researchers attempt to find out more about cellular and molecular details of this problems. Interestingly, the prevalence of the neurological disorders is high in western countries and some evidences show that obesity and diabetes have correlation with occurrence of the neuropathological conditions. Overnutrition or high calorie intake are the most important factors which can accelerate or trigger the pathological circumstances in the CNS. This review focuses on the various lipids and their functions in normal and high calorie intake conditions. We summarize roles of various lipids in the neurodegenretaive e.g. AD and neuropsychiatric e.g. bipolar disorders.
Article
TheWestern world has witnessed a tremendous increase in the occurrence of allergy and autoimmunity in the second half of the 20th century. Extensive efforts have beenmade to explain this phenomenon and various hypotheses have been formulated. Among them, two concepts have attracted the most attention: the "hygiene hypothesis," identifying the reduced exposure to environmental microorganisms as a driving force behind the observed epidemiological trends; and the "diet hypotheses," pointing to the importance of changes in our dietary habits. In this review, we discuss the interplay between theWestern diet, microbiota, and inflammatory conditions, with particular emphasis on respiratory diseases. This is followed by an in-depth overview of the immunomodulatory potential of different dietary fatty acids. We conclude by identifying the outstanding questions, which, if answered, could shed further light on the impact of dietary habits on immunity and interconnect itwith postulates proposed by the hygiene hypothesis. Linking these two concepts will be an important step towards understanding howWestern lifestyle shapes disease susceptibility.
Article
Full-text available
Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture, suggesting that they may play an important role in the pathogenesis of atherosclerosis. Moreover, atherosclerotic lesions contain the Th1-type cytokine IFN-gamma, a potentiator of atherosclerosis. The present study demonstrates the differential expression of the 3 IFN-gamma-inducible CXC chemokines--IFN-inducible protein 10 (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha chemoattractant (I-TAC)--by atheroma-associated cells, as well as the expression of their receptor, CXCR3, by all T lymphocytes within human atherosclerotic lesions in situ. Atheroma-associated endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages (MO) all expressed IP-10, whereas Mig and I-TAC were mainly expressed in ECs and MO, as detected by double immunofluorescence staining. ECs of microvessels within lesions also expressed abundant I-TAC. In vitro experiments supported these results and showed that IL-1beta, TNF-alpha, and CD40 ligand potentiated IP-10 expression from IFN-gamma-stimulated ECs. In addition, nitric oxide (NO) treatment decreased IFN-gamma induction of IP-10. Our findings suggest that the differential expression of IP-10, Mig, and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions during atherogenesis.
Article
Full-text available
A mutation in the msbB gene of Escherichia coli results in the synthesis of E. coli lipopolysaccharide (LPS) that lacks the myristic acid moiety of lipid A. Although such mutant E. coli cells and their purified LPS have a greatly reduced ability to stimulate human immune cells, a minor reduction in the mouse inflammatory response is observed. When the msbB mutation is transferred into a clinical isolate of E. coli, there is a significant loss in virulence, as assessed by lethality in BALB/c mice. When a cloned msbB gene is provided to functionally complement the msbB mutant, virulence returns, providing direct evidence that the msbB gene product is an important virulence factor in a murine model of E. coli pathogenicity. In the genetic background of the clinical E. coli isolate, the msbB mutation also results in filamentation of the cells at 37 degrees C but not at 30 degrees C, a reduction in the level of the K1 capsule, an increase in the level of complement C3 deposition, and an increase in both opsonic and nonopsonic phagocytosis of the msbB mutant, phenotypes that can help to explain the loss in virulence. The demonstration that the inhibition of msbB gene function reduces the virulence of E. coli in a mouse infection model warrants further investigation of the msbB gene product as a novel target for antibiotic therapy.
Article
Full-text available
Results from our previous studies demonstrated that activation of Toll-like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is sufficient to induce nuclear factor kappaB activation and expression of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. Thus, we determined whether these fatty acids modulate LPS-induced signaling pathways and COX-2 expression in monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not unsaturated fatty acids (UFAs), induce nuclear factor kappaB activation and expression of COX-2 and other inflammatory markers. This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS. However, UFAs fail to inhibit COX-2 expression induced by activation of signaling components downstream of Tlr4. Together, these results suggest that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Furthermore, these results suggest a possibility that propensity of monocyte/macrophage activation is modulated through Tlr4 by different types of free fatty acids, which in turn can be altered by kinds of dietary fat consumed.
Article
Full-text available
Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant chemokine CXCL10, also termed Interferon (IFN)-gamma -inducible protein (IP)-10 is pathogenetically involved in several immunoinflammatory and autoimmune diseases. IFN-gamma and IP-10 were quantified by solid-phase ELISA in sera of patients with either newly diagnosed or long-term Type I (insulin-dependent) diabetes mellitus, and in sera of their healthy first degree relatives. The latter were subdivided into "low" and "high" risk prediabetic subjects depending on whether they were negative or positive for the anti-beta-cell autoantibodies ICA and GAD. Compared with healthy control subjects (18%, 9/50), those with a low risk of disease (21%, 5/24) and the group of patients with long-term Type I diabetes (24%, 12/50), IP-10 was found more frequently and at increased concentrations in both newly diagnosed Type I diabetic patients (84%, 42/50) and in those with a high risk of disease (73%, 16/22); in the latter, the IP-10 concentrations correlated with those of IFN-gamma. Circulating IP-10 concentrations is increased in patients with Type I diabetes, but only during the early and subclinical stage of the disease.
Article
Full-text available
To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-kappaB (NF-kappaB) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-kappaB, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-kappaB binding activity in the MNC nuclear extracts increased to 163 +/- 17% and 144 +/- 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-kappaB p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 +/- 1.1% at baseline to 4.3 +/- 1.9% and 2.7 +/- 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flow-mediated vasodilation of the brachial artery.
Article
Full-text available
We investigated the association of several chemokines with the risk of stable coronary heart disease (CHD) in a large case-control study after adjustment for other established risk factors. Furthermore, we analyzed their correlation with various acute-phase proteins, inflammation-associated cytokines, and an adhesion molecule. We included 312 patients aged 40 to 68 years with angiographically confirmed and stable CHD and 472 age- and gender-matched controls in this study. The main outcome measure was the odds ratio (OR) for CHD associated with increased levels of interferon (INF)-inducible protein of 10 kd (IP-10), interleukin (IL)-8, regulated on activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammation protein 1alpha (MIP-1alpha), or eotaxin determined by rigidly evaluated sandwich ELISAs. Serum levels of IP-10 and IL-8 were higher, and serum levels of RANTES were lower in CHD patients when compared with age- and gender-matched controls. In addition, values in the second and top tertile of IP-10 and IL-8 were associated with an increased OR for CHD when compared with values in the bottom tertile [OR for IP-10 (top tertile) was 2.62 (95% CI, 1.79 to 3.85) in the age- and gender-adjusted model and 1.93 (95% CI, 1.23 to 3.04) in the fully adjusted model, and for IL-8, the OR was 1.77 (95% CI, 1.20 to 2.59) and 1.53 (95% CI, 0.98 to 2.39), respectively]; increased RANTES values were associated with a lower OR for CHD [OR, 0.67 (95% CI, 0.47 to 0.96) and 0.61 (95% CI, 0.40 to 0.94)]. Furthermore, positive correlations of IP-10 and IL-8 with several acute-phase proteins or inflammation-associated cytokines were evident, and positive correlations for IP-10 plasma viscosity and intercellular adhesion molecule 1 were also present. The current study suggests that there may be no universal upregulation of chemokines in CHD-associated inflammation but different upregulation of IP-10 and IL-8 versus downregulation of RANTES; there was no clear disease association for MCP-1, MIP-1alpha, or eotaxin.
Article
Full-text available
The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.
Article
Full-text available
Chemokines play an essential role in the progression of rheumatoid arthritis (RA). In the present study we examined the expression and regulatory mechanisms of IFN-gamma inducible protein (IP)-10 in RA synovitis. RA synovial fluid contained greater amounts of IP-10 than did synovial fluid from patients with osteoarthritis. Immunolocalization analysis indicated that IP-10 was associated mainly with infiltrating macrophage-like cells, and fibroblast-like cells in the RA synovium. The interaction of activated leukocytes with fibroblast-like synoviocytes resulted in marked increases in IP-10 expression and secretion. Moreover, induction of IP-10 was mediated via specific adhesion molecules, as indicated by the finding that both anti-integrin (CD11b and CD18) and intercellular adhesion molecule-1 antibodies significantly inhibited IP-10 induction. These results suggest that IP-10 expression within inflamed joints appears to be regulated not only by inflammatory cytokines but also by the physical interaction of activated leukocytes with fibroblast-like synoviocytes, and that IP-10 may contribute to the recruitment of specific subpopulations of T cells (Th1 type) from the bloodstream into the synovial joints.
Article
Full-text available
The chemokines monocyte chemoattractant protein-1 (MCP-1), IL-8 and interferon-gamma-inducible protein-10 (IP-10) are released by adipocytes and appear to be involved in atherosclerosis. We hypothesised that these chemokines may be risk factors for the development of type 2 diabetes. Using a case-cohort design based on data from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Kooperative Gesundheitsforschung in der Region Augsburg/Cooperative Health Research in the Region of Augsburg (KORA Augsburg) study, chemokine levels at baseline were analysed in 526 individuals with and 1,695 individuals without incident type 2 diabetes. The mean follow-up time was 10.8 years. MCP-1 was associated with type 2 diabetes, largely independently of classic risk factors, whereas various clinical and metabolic parameters as well as lifestyle factors were major confounders of the association of IL-8 and IP-10 with type 2 diabetes. Further adjustment for C-reactive protein (CRP) and IL-6 had no impact on the observed associations. The hazard ratio (HR) for subjects with systemic concentrations of all three chemokines (MCP-1, IL-8 and IP-10) above the respective median compared with those with all chemokines below or equal to the median was 1.79 (95% CI 1.18-2.72) and was comparable with the HR for elevated CRP and IL-6 together (adjusted for age, sex, survey, BMI, systolic blood pressure, total cholesterol:HDL cholesterol ratio, physical activity, alcohol intake, smoking and parental history of diabetes). Elevated concentrations of MCP-1, IL-8 and IP-10 are associated with incident type 2 diabetes. Whereas the association of IL-8 and IP-10 with diabetes was attenuated by multivariable adjustment, high MCP-1 levels contributed to diabetes risk independently of previously described clinical, metabolic and immunological risk factors.
Article
Full-text available
Previous studies demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. Using an in vitro coculture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we previously demonstrated that saturated fatty acids (FAs) and tumor necrosis factor (TNF)-alpha derived from adipocytes and macrophages, respectively, play a major role in the coculture-induced inflammatory changes. Coculture of adipocytes and macrophages resulted in the activation of nuclear factor-kappaB (NF-kappaB), a primary regulator of inflammatory responses, in both cell types. Pharmacological inhibition of NF-kappaB markedly suppressed the coculture-induced production of proinflammatory cytokines and adipocyte lipolysis. Peritoneal macrophages obtained from Toll-like receptor 4 (TLR4) mutant mice exhibited marked attenuation of TNFalpha production in response to saturated FAs. Notably, coculture of hypertrophied adipocytes and TLR4-mutant macrophages resulted in marked inhibition of proinflammatory cytokine production and adipocyte lipolysis. We also observed that endogenous FAs, which are released from adipocytes via the beta3-adrenergic stimulation, resulted in the activation of the TLR4/NF-kappaB pathway. These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappaB activation.
Article
Regulation of angiogenesis is dependent on the net biological balance between expression of angiogenic and angiostatic molecules in the injured tissue. Using a canine model of myocardial ischemia/reperfusion, we demonstrated that expression of the angiostatic chemokine interferon‐ inducible protein (IP‐10) peaked at 1–3 h of reperfusion and virtually disappeared by 24 h of reperfusion. IP‐10 mRNA and protein were localized in the venular endothelium during early reperfusion of ischemic myocardial segments and were not detected after 24 h. Endothelial cell proliferation was first noted after 24 h of reperfusion, and αv β3 expressing neovessels were seen after 72–120 h of reperfusion, suggesting that neovascularization began only when IP‐10 expression was markedly reduced. Isolated canine venular endothelial cells expressed high levels of IP‐10 and IL‐8 mRNA upon stimulation with tumor necrosis factor (TNF) ‐α and endotoxin. Transforming growth factor (TGF) ‐β, but not interleukin (IL) ‐10, decreased TNF‐α‐mediated IP‐10 expression in canine endothelial cells. In contrast, TNF‐α‐mediated IL‐8 induction was not affected by incubation with IL‐10 or TGF‐β. Induction of angiostatic factors, such as IP‐10, in the first hours following injury may be important in inhibiting premature neovessel formation, until the appropriate supportive matrix is present. IP‐10 down‐regulation by active TGF‐β may mediate the onset of neovascularization by allowing unopposed VEGF‐ and IL‐8‐mediated angiogenic activity.
Article
It is well established that cardiovascular disease has an inflammatory component. The present narrative review explores the role of adipose tissue distribution, morphology, and function as potential mediators of the link between inflammation and cardiovascular disease. Evidence that abdominal obesity is a key driving force behind a constellation of atherothrombotic inflammatory abnormalities linked to insulin resistance and often referred to as the metabolic syndrome is also reviewed. It is also proposed that the amount of visceral adipose tissue and the liver fat content are important factors responsible for the link between abdominal obesity and features of the metabolic syndrome. It is suggested that the inflammatory profile associated with excess visceral adipose tissue/liver fat may be a consequence of the relative inability of subcutaneous adipose tissue to expand through hyperplasia and to act as a protective metabolic sink storing the chronic energy surplus resulting from a positive energy balance (overnutrition or lack of physical activity or both). In this model, the inflammatory profile often observed among sedentary overweight/obese individuals with an excess of visceral adipose tissue/liver fat may be a consequence of a more primary defect in subcutaneous adipose tissue. On that basis, it is proposed that therapeutic strategies relieving the stress for storage of a chronic energy surplus in the subcutaneous adipose tissue (reduced caloric intake, increase in energy expenditure, pharmacotherapy) should induce a substantial loss of visceral adipose tissue and of ectopic fat depots such as the liver, thereby substantially reducing inflammation.
Article
Interferon-gamma inducible protein 10 kD (IP-10) is a highly inducible, primary response gene that belongs to the C-X-C chemokine superfamily. Despite the original cloning of IP-10 in 1985, its biological functions are still unclear although accumulating reports indicate that it is a pleiotropic molecule capable of eliciting potent biological effects, including stimulation of monocytes, natural killer and T-cell migration, regulation of T-cell and bone marrow progenitor maturation, modulation of adhesion molecule expression as well as inhibition of angiogenesis. More interest is now likely to be focused on IP-10 due to the recent cloning of an IP-10 receptor. This paper aims to highlight our current knowledge of IP-10 and its homologues as well as defining its likely involvement in regulating fibroproliferation following inflammatory lung injury.
Article
A finding commonly observed in human immunodeficiency virus type 1 (HIV-1)-infected patients is invasion of the brain by activated T cells and infected macrophages, eventually leading to the development of neurological disorders and HIV-1-associated dementia. The recruitment of T cells and macrophages into the brain is likely the result of chemokine expression. Indeed, earlier studies revealed that levels of different chemokines were increased in the cerebrospinal fluid of HIV-1-infected patients whereas possible triggers and cellular sources for chemokine expression in the brain remain widely undefined. As previous studies indicated that HIV-1 Tat, the retroviral transactivator, is capable of inducing a variety of cellular genes, we investigated its capacity to induce production of chemokines in astrocytes. Herein, we demonstrate that HIV-1 Tat72aa is a potent inducer of MCP-1, interleukin-8 (IL-8), and IP-10 expression in astrocytes. Levels of induced IP-10 protein were sufficiently high to induce chemotaxis of peripheral blood lymphocytes. In addition, Tat72aa induced IL-8 expression in astrocytes. IL-8 mRNA induction was seen less then 1 h after Tat72aastimulation, and levels remained elevated for up to 24 h, leading to IL-8 protein production. Tat72aa-mediated MCP-1 and IL-8 mRNA induction was susceptible to inhibition by the MEK1/2 inhibitor UO126 but was only modestly decreased by the inclusion of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190. In contrast, Tat-mediated IP-10 mRNA induction was suppressed by SB202190 but not by the MEK1/2 inhibitor UO126. These findings indicate that MAPKs play a major role in Tat72aa-mediated chemokine induction in astrocytes.
Article
The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data.
Nuclear factor kappa B (NF-kappaB)/Rel proteins are dimeric, sequence-specific transcription factors involved in the activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. In unstimulated cells, NF-kappaB is sequestered in an inactive form in the cytoplasm bound to inhibitory IkappaB proteins. Stimulation leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus and activate the transcription of its target genes. The multisubunit IkappaB kinase (IKK) responsible for the inducible phosphorylation of IkappaB appears to be the initial point of convergence for most stimuli that activate NF-kappaB. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which phosphorylate IkappaB at sites phosphorylated in vivo. Gene knockout studies indicate that IKKbeta is primarily responsible for the activation of NF-kappaB in response to proinflammatory stimuli, whereas IKKalpha is essential for keratinocyte differentiation. The activity of IKK is regulated by phosphorylation. IKK contains a regulatory subunit, IKKgamma, which is critical for activation of IKK and is postulated to serve as a recognition site for upstream activators. When phosphorylated, the IKK recognition site on IkappaBalpha serves as a specific recognition site for the kappa-TrCP-like component of a Skp1-Cullin-F-box-type E3 ubiquitin-protein ligase. A variety of other signaling events, including phosphorylation of NF-kappaB, phosphorylation of IKK, new synthesis of IkappaBs, and the processing of NF-kappaB precursors provide mechanisms of modulating the amount and duration of NF-kappaB activity.
Article
IFN-gamma-inducible protein 10 (IP-10, CXCL10), a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is a chemoattractant for activated T cells. Expression of IP-10 is seen in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells into sites of tissue inflammation. To determine the in vivo function of IP-10, we constructed an IP-10-deficient mouse (IP-10(-/-)) by targeted gene disruption. Immunological analysis revealed that IP-10(-/-) mice had impaired T cell responses. T cell proliferation to allogeneic and antigenic stimulation and IFN-gamma secretion in response to antigenic challenge were impaired in IP-10(-/-) mice. In addition, IP-10(-/-) mice exhibited an impaired contact hypersensitivity response, characterized by decreased ear swelling and reduced inflammatory cell infiltrates. T cells recovered from draining lymph nodes also had a decreased proliferative response to Ag restimulation. Furthermore, IP-10(-/-) mice infected with a neurotropic mouse hepatitis virus had an impaired ability to control viral replication in the brain. This was associated with decreased recruitment of CD4(+) and CD8(+) lymphocytes into the brain, reduced levels of IFN-gamma and the IFN-gamma-induced chemokines monokine induced by IFN-gamma (Mig, CXCL9) and IFN-inducible T cell alpha chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of virus-specific IFN-gamma-secreting CD8(+) cells in the spleen, and reduced levels of demyelination in the CNS. Taken together, our data suggest a role for IP-10 in both effector T cell generation and trafficking in vivo.
Article
Chemokines are multifunctional mediators mainly responsible for leukocyte recruitment to inflamed tissues. Cytokines of the CXC family, however, also have a pivotal role in the control of inflammation and angiogenesis, as a result of the shared expression of their specific receptors by leukocytes and endothelial cells. Although the mechanisms of activity of angiogenic chemokines are known, the identification of those responsible for CXC chemokine-mediated angiostatic effects has been difficult. The recent discovery of a novel variant of CXCR3 (CXCR3-B) as a common receptor for all four angiostatic chemokines (CXCL4, CXCL9, CXCL10 and CXCL11) has enabled a better understanding of how CXC chemokines not only influence the sequential participation of inflammatory cells but also regulate, in a coordinate way, the inflammatory reaction leading to angiogenesis, tissue repair and new tissue generation. Dysregulation of this fine regulatory network can lead to abnormalities, such as chronic inflammation, dysplastic transformation and even tumor development and spreading. Thus, targeting of these chemokines or their receptors might provide a successful therapeutic approach in chronic inflammatory and neoplastic diseases.
Article
The adipocyte exerts an important role in energy homeostasis, both as depot for energy-rich triglycerides and as a source for metabolic hormones. Adipocytes also contribute to inflammation and the innate immune response. Although it can be physiologically beneficial to combine these two functions in a single cell type under some circumstances, the proinflammatory signals emanating from adipocytes in the obese state can have local and systemic effects that promote atherosclerosis and insulin resistance. The transcriptional machinery in the adipocyte that mediates these pro-inflammatory responses has remained poorly characterized to date. In particular, no information is currently available on the NF-kappaB family of transcription factors. Here, we show that adipogenesis is associated with changes in amount and subunit composition of the NF-kappaB complexes. NF-kappaB subunits p65 (RelA), p68 (RelB), and IkappaB are upregulated during fat cell differentiation. Correspondingly, basal NF-kappaB nuclear gel shift and luciferase reporter assays are induced in parallel during differentiation. Surprisingly, endotoxin sensitivity of the classical NF-kappaB pathway is substantially delayed and attenuated despite increased overall inflammatory response in the mature adipocyte, as judged by induction of IL-6 and TNF-alpha. As a reflection of the constitutively elevated NF-kappaB activity in the mature adipocyte, adipocytes (but not preadipocytes) exert a strong inflammatory stimulus on macrophages in vitro, suggesting a cross talk between adipocytes and interstitial macrophages in adipose tissue in vivo. These effects are mediated by a secretory product of adipocytes that is unlikely to be IL-6 or TNF-alpha.
Article
Recent studies have shown the important role of proinflammatory cytokines and chemokines in the pathogenesis of atherosclerosis and diabetes mellitus(DM). Interferon-inducible protein of 10 kD (IP-10/ CXCL10), a member of the C-X-C chemokine superfamily, is a potent chemoattractant for activated T lymphocytes and is reported to be involved in various disease states including atheroma plaque formation, inhibition of tumor angiogenesis and maintenance of podocyte function. However, the involvement of IP-10 in type 2 DM, especially in its vascular and renal complications, is largely unknown. To elucidate the etiopathological role of IP-10 in type 2 DM, we measured the concentrations of IP-10 together with IFN-gamma, TNF-alpha, IL-18, IL-6 and MCP-1 in plasma samples from 103 type 2 DM patients with various degrees of nephropathy. A significant difference in the plasma level of IP-10 was observed between the patients and the control subjects (183.3+/-12.5 pg/m/ vs 65.6+/-9.3 pg/ml, p<0.05). IP-10 correlated IL-18, IL-6, TNF-alpha and MCP-1. The IFN-gamma level was below the detectable range. IP-10 levels became higher with the progression of nephropathy : IP-10 levels were 148.9+/-14.5, 174.2+/-17.2 and 231.9+/-31.3 pg/m/ in patients with an urinary albumin creatinine ratio of <30, 30 to 300 and >300 microg/mg Cr, respectively. Similarly, IL-18, IL-6, MCP-1 and TNF-alpha levels in patients with overt albuminuria were significantly higher as compared with those without albuminuria (IL-18, 367.3 45.6 vs 203.5+/-17.6 pg/ml; IL-6, 1.61+/-0.26 vs 0.87+/-0.13 pg/ml; TNF-alpha, 1.83+/-0.48 vs 0.61+/-0.07 pg/ml; p<0.05, respectively) in consistent with previous reports. These results suggested that IP-10 may have an etiopathogenic role in type2 DM and diabetic nephropathy as one of the downstream effectors of proinflammatory cytokines.
Article
Obesity is associated with an increased risk for cardiovascular disease. Although it is known that white adipose tissue (WAT) produces numerous proinflammatory and proatherogenic cytokines and chemokines, it is unclear whether adipose-derived chemotactic signals affect the chronic inflammation in atherosclerosis. Histological examination showed that perivascular WAT (pWAT) is in close proximity to vascular walls, particularly at sites that have a tendency to develop atherosclerosis. In rodents, the amount of pWAT is markedly increased by a high-fat diet. At a functional level, supernatant from subcutaneous and pWAT strongly induced the chemotaxis of peripheral blood leukocytes. The migration of granulocytes and monocytes was mostly mediated by interleukin-8 and monocyte chemoattractant protein-1, respectively, whereas both chemokines contributed to the migration of activated T cells. Moreover, pWAT produces these chemokines, as shown by immunohistochemistry and by explant culture. The accumulation of macrophages and T cells at the interface between pWAT and the adventitia of human atherosclerotic aortas may reflect this prochemotactic activity of pWAT. Human pWAT has chemotactic properties through the secretion of different chemokines, and we propose that pWAT might contribute to the progression of obesity-associated atherosclerosis.
Article
Monocyte proinflammatory activity has been demonstrated in obesity, insulin resistance, and type 2 diabetes, metabolic conditions that are frequently associated with elevated levels of nonesterified fatty acids (NEFA). We therefore tested the hypothesis that NEFA may induce monocyte inflammation. Monocytes exposed to NEFA for 2 days demonstrated a dose-related increase in intracellular reactive oxygen species (ROS) formation and adhesion to endothelial cells. All of these effects were inhibited by the coaddition of antioxidants such as glutathione or butylated hydroxytoluene, by inhibition of ROS generation by NADPH oxidase inhibitors, and by inhibition of protein kinase C, a recognized stimulator of NAPDH oxidase. Monocytes exposed to NEFA also demonstrated a significant increase in CD11b message expression. Stimulation of monocyte adhesion to endothelial cells by NEFA was inhibited by addition of neutralizing antibodies to either CD11b or CD18. Finally, surface expression of CD11b increased significantly on monocytes as measured by flow cytometry, after their incubation with NEFA. These studies indicate that elevated concentrations of NEFA may enhance integrin facilitated monocyte adhesion to endothelial cells and these effects appear mediated, in part, through activation of NADPH oxidase and oxidative stress.
Article
Obesity is associated with increased macrophage infiltration of adipose tissue, and these macrophages may be an important component of the chronic inflammatory response playing a crucial role in the development of insulin resistance. This prompts the question as to how macrophages infiltrate obese adipose tissue. In this issue of the JCI, Weisberg et al. show the importance of C-C motif chemokine receptor 2 (CCR2) in macrophage recruitment to adipose tissue and the development of obesity and its complications.
Article
Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-kappaB) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-kappaB inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity.
Article
Obesity leads to a proinflammatory state with immune responses that include infiltration of adipose tissue with macrophages. These macrophages are believed to alter insulin sensitivity in adipocytes, but the mechanisms that underlie this effect have not been characterized. We have explored the interaction between macrophages and adipocytes in the context of both indirect and direct coculture. Macrophage-secreted factors blocked insulin action in adipocytes via downregulation of GLUT4 and IRS-1, leading to a decrease in Akt phosphorylation and impaired insulin-stimulated GLUT4 translocation to the plasma membrane. GLUT1 was upregulated with a concomitant increase in basal glucose uptake. These changes recapitulate those seen in adipose tissue from insulin-resistant humans and animal models. TNF-alpha-neutralizing antibodies partially reversed the insulin resistance produced by macrophage-conditioned media. Peritoneal macrophages and macrophage-enriched stromal vascular cells from adipose tissue also attenuated responsiveness to insulin in a manner correlating with inflammatory cytokine secretion. Adipose tissue macrophages from obese mice have an F4/80(+)CD11b(+)CD68(+)CD14(-) phenotype and form long cellular extensions in culture. Peritoneal macrophages take on similar characteristics in direct coculture with adipocytes and induce proinflammatory cytokines, suggesting that macrophage activation state is influenced by contact with adipocytes. Thus both indirect/secreted and direct/cell contact-mediated factors derived from macrophages influence insulin sensitivity in adipocytes.
Article
JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic β-cells. In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids. • diabetes • insulin gene expression • lipotoxicity • obesity
Article
Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.