Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance
ABSTRACT Activated innate immunity is thought to be involved in the pathogenesis of metabolic syndrome and type 2 diabetes. Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response. We sought to determine whether an elevated IL-18 concentration was a risk predictor for metabolic syndrome in a community population independent of obesity and hyperinsulinemia.
A representative general population, aged 27 to 77 years, without clinical diabetes was studied for clinical and biochemical risk factors for metabolic syndrome. Serum IL-18 concentration measured in 955 subjects correlated with metabolic syndrome traits including body mass index (BMI), waist circumference, triglyceride, high-density lipoprotein (inversely), and fasting glucose and insulin levels (all P<0.001). Mean IL-18 levels rose progressively with the increasing number of metabolic risk factors (ANOVA P<0.001). After adjusting for age, gender, BMI, and insulin levels, increasing IL-18 tertiles were associated with an odds ratio for metabolic syndrome of 1.0, 1.42, and 2.28, respectively (P trend=0.007). The graded risk relation was even stronger in nonobese subjects and not attenuated when adjusted for C-reactive protein and IL-6 levels.
Our findings support the hypothesis that activation of IL-18 is involved in the pathogenesis of the metabolic syndrome.
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ABSTRACT: Circulating levels of leptin are elevated in type-2 diabetes mellitus (T2DM) and leptin plays a role in immune responses. Elevated circulating IL-18 levels are associated with clinical complications of T2DM. IL-18 regulates cytokine secretion and the function of a number of immune cells including T-cells, neutrophils and macrophages and as such has a key role in immunity and inflammation. Pro-inflammatory monocytes exhibiting elevated cytokine secretion are closely associated with inflammation in T2DM, however, little is known about the role of leptin in modifying monocyte IL-18 secretion. We therefore aimed to investigate the effect of leptin on IL-18 secretion by monocytes. We report herein that leptin increases IL-18 secretion in THP-1 and primary human monocytes but has no effect on IL-18 mRNA. Leptin and LPS signalling in monocytes occurs by overlapping but distinct pathways. Thus, in contrast to a strong stimulation by LPS, leptin has no effect on IL-1β mRNA levels or IL-1β secretion. In addition, LPS stimulates the secretion of IL-6 but leptin did not whereas both treatments up regulate IL-8 secretion from the same cells. Although leptin (and LPS) has a synergistic effect with exogenous ATP on IL-18 secretion in both THP-1 and primary monocytes, experiments involving ATP assays and pharmacological inhibition of ATP signalling failed to provide any evidence that endogenous ATP secreted by leptin-stimulated monocytes was responsible for enhancement of monocyte IL-18 secretion by leptin. Analysis of the action of caspase-1 revealed that leptin up regulates caspase-1 activity and the effect of leptin on IL-18 release is prevented by caspase-1 inhibitor (Ac-YVAD-cmk). These data suggest that leptin activates IL-18 processing rather than IL-18 transcription. In conclusion, leptin enhances IL-18 secretion via modulation of the caspase-1 inflammasome function and acts synergistically with ATP in this regard. This process may contribute to aberrant immune responses in T2DM and other conditions of hyperleptinemia.Cytokine 02/2014; 65(2):222-30. DOI:10.1016/j.cyto.2013.10.008 · 2.87 Impact Factor
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ABSTRACT: The postprandial state is hypothesised to be proinflammatory and prooxidative, but the relative contributions of fat versus carbohydrate are unclear. Therefore, we examined inflammation and oxidative stress responses in serum and skeletal muscle before and after 1000 kcal meals, which were high in either fat or carbohydrate in 15 healthy individuals. Serum and muscle expression of IL6 was elevated 3 hours after each meal, independently of macronutrient composition (P < 0.01). Serum IL18 was decreased after high-fat meal only (P < 0.01). Plasma total antioxidative status and muscle Cu/Zn-superoxide dismutase were decreased after high-carbohydrate meal only (P < 0.05). We conclude that a high-carbohydrate meal may evoke a greater postprandial oxidative stress response, whereas both fat and carbohydrate increased IL6. We speculate that the observed increases in postprandial IL6, without increases in any other markers of inflammation, may indicate a normal IL6 response to enhance glucose uptake, similar to its role postexercise.Journal of nutrition and metabolism 01/2012; 2012:238056. DOI:10.1155/2012/238056
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ABSTRACT: We demonstrate for the first time that the pro-inflammatory cytokine interleukin (IL)-18 stimulates rapid and significant proliferation of SMC derived from human saphenous vein (VSMC), but not coronary artery. IL-18 also stimulates VSMC growth. Further investigations revealed that IL-18-induced VSMC proliferation was Wnt inducible secreted protein-1 (WISP1) dependent. In addition to inducing its own expression via phosphatidylinositol 3-kinase/Akt-dependent IKK/NF-κB activation, IL-18 stimulated glycogen synthase kinase 3β phosphorylation and degradation, β-catenin nuclear translocation and stabilization, T-cell factor-lymphoid enhancer binding factor (TCF-LEF) activation, and WISP1 induction. Moreover, WISP1 induced its own expression, and that of survivin and multiple matrix metalloproteinases via β-catenin/TCF-LEF interaction. WISP1 also activated AP-1, but not NF-κB, and induced matrix metalloproteinase (MMP)9 transcription in part via AP-1. Interestingly, WISP1 failed to regulate tissue inhibitors of matrix metalloproteinases (TIMP) expression. These novel findings indicate that IL-18 induces a series of signaling events that result in WISP1-mediated VSMC proliferation, survival and MMP induction that are key components of vein graft stenosis and this may be amplified by IL-18 and WISP1 autoregulation and cross-regulation.Journal of Cellular Physiology 12/2011; 226(12):3303-15. DOI:10.1002/jcp.22676 · 3.87 Impact Factor