| Abstract |
Adipose tissue acts as an endocrine organ producing a number of molecules with an important role in the regulation of metabolism and inflammation. Adiponectin is the most abundant gene product in adipose tissue and circulates at high concentrations in the blood. Adiponectin levels are decreased in obesity, in TIIDM and in patients with CAD. It is believed that adiponectin has protective actions in the initiation and progression of atherosclerosis and the metabolic syndrome through anti-inflammatory and anti-diabetic effects. The anti-inflammatory effects of adiponectin are believed to be exerted via macrophages, through suppression of the production of pro-inflammatory cytokines in response to LPS. In this report, we provide experimental evidence that globular adiponectin (gAd) is a powerful inducer of TNFα and IL6 secretion in the THP-1 macrophage cell line, in primary human peripheral macrophages and in primary mouse peritoneal macrophages. To explain how the apparent pro-inflammatory action of gAd ends up in an anti-inflammatory effect, we suggested that the anti-inflammatory effect of adiponectin is due to an induction of macrophage tolerance to pro-inflammatory stimuli, including its own. We also suggest that this effect of gAd on macrophage sensitivity to pro-inflammatory stimuli is dose-dependent. Indeed, pre-exposure of macrophages to high concentrations of gAd (that correspond to lean subjects) rendered them tolerant to further gAd exposure or to other pro-inflammatory stimuli, such as TLR3 ligand polyI:C and TLR4 ligand LPS. Pre-exposure to low concentrations of gAd (that correspond to obese subjects) and re-exposure to high levels of gAd unmasked its pro-inflammatory properties. Also, gAd induced NFkB activation and tolerance to further gAd or LPS exposure. Our data suggest that constant presence of adiponectin in the circulation in high levels renders macrophages resistant to its own action and to other pro-inflammatory stimuli. CRH and Urocortins are other major regulators of the inflammatory process. When released at the site of inflammation from nerve terminals, epithelial and immune cells, these peptides affect directly the immune system at the level of macrophage activation, exerting pro-inflammatory effects. In this report we examine the effect of CRH and UCN2 on the regulation of adiponectin receptors AdipoR1 and AdipoR2 and on the adiponectin and LPS-induced production of pro-inflammatory cytokines in macrophages. Expression levels of AdipoR1 and AdipoR2 were significantly downregulated by CRH and UCN2, in THP-1 monocytes, while pre-incubation of THP-1 macrophages with CRH and UCN2 did not affect the adiponectin and LPS-induced production of pro-inflammatory cytokines.
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Μελέτη της επίδρασης της αδιπονεκτίνης στη διέγερση των μακροφάγων
