Gender-based dimorphic pattern for interleukin-1 receptor antagonist in type 2 diabetes mellitus

Adipose tissue secretes a variety of cytokines, some of which are increased in the serum of obese patients. The anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) is the most highly elevated known cytokine in human obesity, and its serum levels are strongly associated with the degree of insulin resistance in non-diabetic patients. AIM: The present study examined serum levels of IL-1Ra in type 2 diabetic patients (T2DM) and their relationships with three other adipokines (leptin, interleukin-6 [IL-6], adiponectin). Their correlation with anthropometric and biochemical variables was examined, as well as their intraindividual fluctuations. METHODS: Fifty T2DM patients, aged 58+/-13 years, were consecutively recruited among those electively hospitalized for a one-week intensive training course with our Diabetes Education Service. Anthropometric measurements and blood samples were taken after an overnight fast on admission (baseline) and after four days. RESULTS: Mean serum levels of IL-1Ra and leptin, but not of IL-6 and adiponectin, were significantly higher in women than in men (P<0.0006), and this difference persisted after correction for body mass index (BMI) (P<0.0004). In addition, IL-1Ra and leptin were strongly correlated with the BMI (P<0.0004). By contrast, no significant correlations were observed between IL-1Ra and glucose-control parameters. Finally, all four adipokines exhibited wide interindividual variability, but with limited intraindividual fluctuations over the short time period. CONCLUSION: IL-1Ra, leptin and adiponectin serum levels exhibit marked interindividual variation with high intraindividual consistency. A gender-based dimorphic pattern for IL-1Ra, independent of the degree of adiposity and glucose control, was also found

Adipose tissue is a regulated source of interleukin-10

White adipose tissue (WAT) is the source of pro- and anti-inflammatory cytokines and we have recently shown that this tissue is a major source of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1Ra). We now aimed at identifying additional adipose-derived cytokines, which might serve as regulators of IL-1Ra. We demonstrate here for the first time that the antiinflammatory cytokine IL-10 is secreted by human WAT explants and that it is up-regulated by LPS and TNF-alpha in vitro, as well as in obesity in humans (2- and 6-fold increase in subcutaneous and visceral WAT, respectively) and rodents (4-fold increase)

Glucocorticoids aggravate hyperoxia-induced lung injury through decreased nuclear factor-kappa B activity

We previously reported that exposure of mice to hyperoxia is characterized by extensive lung cell necrosis and apoptosis, mild inflammatory response, and elevated circulating levels of corticosterone. Administration of hydroxycortisone acetate during hyperoxia aggravated lung injury. Using adrenalectomized (ADX) and sham-operated (sham) mice, we studied the role of the glucocorticoids in hyperoxia-induced lung injury. Lung damage was attenuated in ADX mice as measured by lung weight and protein and cell content in bronchoalveolar lavage and as seen by light microscopy. Mortality was delayed by 10 h. Nuclear factor-kappaB (NF-kappaB) activity was significantly decreased in lungs of sham mice exposed to hyperoxia but was preserved in ADX mice. There was a correlation between NF-kappaB activity in ADX mice and decreased levels of IkappaBalpha. In contrast, activator protein-1 activity increased similarly in both groups of mice. Levels of interleukin-6 (IL-6), a transcriptional target of NF-kappaB, were higher in bronchoalveolar lavage and serum of ADX than sham mice. However, the protective effect of ADX was not mediated by IL-6, because administration of recombinant human IL-6 to sham mice did not prevent lung damage. These results demonstrate that the adrenal response aggravates alveolar injury and is likely to be mediated by the decrease of NF-kappaB function involved in cell survival

Leptin activates the promoter of the interleukin-1 receptor antagonist through p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa B/PU.1 binding site.

We have recently shown that leptin strongly induces the expression and secretion of the interleukin-1 receptor antagonist (IL-1Ra) [Gabay, Dreyer, Pellegrinelli, Chicheportiche and Meier (2001) J. Clin. Endocrinol. Metab. 86, 783-791] in monocytes. However, the intracellular signalling mechanisms involved remained unknown. We now demonstrate that the activation of the IL-1Ra promoter by leptin is strictly dependent on the presence of the long form of the leptin receptor (OB-Rb), and that it also requires the activation of the p42/44 mitogen-activated protein kinases (MAPKs) as well as the presence of a nuclear factor kappaB (NF-kappa B)/PU.1 composite site at position -80 of the IL-1Ra promoter. Although leptin is capable of activating a NF-kappa B reporter element in transient transfection experiments, the protein complex binding to the NF-kappa B/PU.1 site of the IL-1Ra promoter is not composed of the p65/p50 subunits of NF-kappa B, as is evident in electrophoretic gel mobility-shift experiments. In contrast, a protein complex which does not contain PU.1 binds to this composite element in a leptin-dependent manner. In summary, we characterize the signalling pathway for leptin and OB-Rb involved in the induction of IL-1Ra, involving p42/44 MAPK, and a yet uncharacterized complex of transcription factor(s) binding to a NF-kappa B/PU.1 composite element of the IL-1Ra promoter

Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis?

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