Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler Thromb Vasc Biol

Sir Charles Gairdner Hospital Campus of the Heart Research Institute of Western Australia, and School of Medicine and Pharmacology, University of Western Australia, Nedlands, Perth.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2005; 25(6):1268-73. DOI: 10.1161/01.ATV.0000163843.70369.12
Source: PubMed


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.

Download full-text


Available from: Joe Hung, Nov 06, 2015
    • "The trigger that leads to increased circulating IL-18 in individuals with metabolic syndrome has not been discovered. Initially it was thought to be a byproduct of increased fat mass; however, this correlation was not reproducible (Fischer et al., 2005; Hung et al., 2005). Instead, some studies show that plasma IL-18 levels correlate with triglyceride levels (Trøseid et al., 2009; Vilarrasa et al., 2007) and that IL-18 is increased in the circulation shortly after a high-fat meal, but not after a high-carbohydrate meal (Esposito et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-18 (IL-18) is activated by Caspase-1 in inflammasome complexes and has anti-obesity effects; however, it is not known which inflammasome regulates this process. We found that mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not when mice are fed a HFD with low energy density (high fiber). Furthermore, mice with an activating mutation in NLRP1, and hence increased IL-18, have decreased adiposity and are resistant to diet-induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Thus, NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome.
    No preview · Article · Oct 2015 · Cell metabolism
  • Source
    • "Significantly, circulating IL-18 is elevated in obesity [17], metabolic syndrome [18] and T2DM [19] [20] and elevated IL-18 in T2DM is associated with the development of important clinical complications such a nephropathy [21] and atherosclerosis [22]. In common with IL-1b, IL-18 is synthesised as a pro-peptide which lacks a secretory signal and therefore requires proteolytic processing prior to secretion; this is achieved by casapse-1 [16]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2014 · Cytokine
  • Source
    • "To explain a link between inflammation and insulin resistance, it was proposed that OPN might cause accumulation of the macrophages in adipose tissue and lead to an increased macrophage-related inflammatory activity [19], [40], [41]. Consistent with the previous cross-sectional studies [26], [42], [43], our data also show that the circulating IL-18 and OPN levels increased progressively with the escalating BMI values. After stepwise multiple linear regression analysis both OPN and IL-18 were found to be independently associated with BMI (P<0.05) which indicated that obesity contributed to the upregulation of OPN and IL-18 levels in plasma and in PBMCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteopontin (OPN) and IL-18 are known inflammatory mediators and both participate in a wide range of biological processes linked to immunological disorders. Since an interaction between OPN and IL-18 has not been studied in obesity, we investigated whether: (i) their levels were simultaneously elevated in obese individuals; (ii) OPN was associated with IL-18 in obese individuals and (iii) their levels associated with fasting blood glucose (FBG) and BMI. PBMCs and plasma samples were isolated from 60 individuals including lean as well as overweight and obese individuals. Subcutaneous adipose tissue samples were obtained. OPN and IL-18 were measured by ELISA. OPN and IL-18 mRNA expression was quantified by real time quantitative RT-PCR. Obese individuals exhibited significantly increased circulating OPN levels as compared with lean individuals (obese 2865±101; lean 1681±116 pg/ml; P<0.0001). IL-18 levels were also high in obese individuals (obese 491±39, lean 301±26 pg/ml; P = 0.0009). OPN and IL-18 expression were simultaneously up-regulated (OPN: 5.4-Fold; IL-18: 8.9-Fold; P<0.05) in PBMCs from obese individuals compared to lean group. Adipose tissue from obese individuals had high expression of OPN (7.3-Fold) and IL-18 (9.6-Fold). Plasma OPN levels correlated positively with FBG levels (r = 0.32, P = 0.02). Similarly, IL-18 correlated positively with FBG levels (r = 0.406, P = 0.0042). Stepwise multiple regression analysis showed an independent association of BMI with OPN and IL-18. Interestingly, OPN levels increased progressively with an increase in IL-18 levels (r = 0.52, P = 0.0004). We also examined the regulatory role of IL-18 in OPN secretion from PBMCs. Neutralizing anti-IL-18Rα mAb reduced OPN secretion. These findings represent the first observation that plasma, PBMC and adipose tissue OPN and IL-18 are simultaneously increased and correlate with each other in overweight/obese individuals which may trigger the development of obesity-associated insulin resistance. Moreover, these results provide the direct evidence that IL-18 regulates OPN production in PBMCs.
    Full-text · Article · May 2013 · PLoS ONE
Show more