Interleukin-10 Protects Nitric Oxide–Dependent Relaxation During Diabetes

Abstract

Interleukin (IL)-10, an anti-inflammatory cytokine, preserves endothelial function during acute inflammation. We tested the hypotheses that IL-10 plays a protective role in blood vessels during diabetes by suppressing impairment of endothelium-dependent relaxation and that protection by IL-10 is mediated by effects on superoxide (O 2 ؊ ). Streptozotocin (150 mg/kg i.p.) or citrate buffer was injected into IL-10 -deficient (IL-10 ؊/؊ ) mice and wild-type controls (IL-10 ؉/؉ ). In IL-10 ؉/؉ and IL-10 ؊/؊ mice, blood glucose levels were ϳ120 mg/dl after citrate administration and ϳ400 mg/dl after streptozotocin administration. Vasorelaxation was examined in arteries in vitro 12-16 weeks later. Maximum relaxation to acetylcholine (30 mol/l) was 88 ؎ 3% (means ؎ SE) in nondiabetic mice and 84 ؎ 3% in diabetic IL-10 ؉/؉ mice (P > 0.05). Thus, at this time point, diabetes did not impair endothelium-dependent relaxation in vessels in wild-type mice. In contrast, maximum relaxation in vessels from diabetic IL-10 ؊/؊ mice was significantly decreased (74 ؎ 5%) compared with nondiabetic IL-10 ؊/؊ mice (93 ؎ 2%, P < 0.05). Superoxide dismutase with polyethylene glycol (PEG-SOD) restored impaired responses to acetylcholine to levels seen in controls. Responses to acetylcholine also were improved by allopurinol (an inhibitor of xanthine oxidase) in vessels from diabetic IL-10 ؊/؊ mice. Thus, diabetes produces greater impairment of relaxation to acetylcholine in IL-10 ؊/؊ mice than in IL-10 ؉/؉ mice. These findings provide direct evidence that IL-10 impedes mechanisms of endothelial dysfunction during diabetes. Restoration of vasorelaxation with PEG-SOD or allopurinol suggests that the mechanism(s) by which IL-10 preserves endothelium-dependent vasorelaxation involves O 2 ؊ , perhaps by reducing production of O 2 ؊ by xanthine oxidase.

Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway

“…Consistent with previous studies (3,15,16,42), we have found that IL-10 plays a protective role in the alterations of vascular reactivity. Regional differences in cytokine-induced release and responsiveness to mediators appear to contribute to the dilator or constrictor responses observed in a specific vascular bed (42).…”

“…Exogenous IL-10 prevents proliferative vasculopathy by inhibiting inflammatory cell infiltration, smooth muscle cell proliferation, and chemokine expression (3,27). This cytokine counteracts the endothelial dysfunction induced by angiotensin II, lipopolysaccharide, and endothelin (ET)-1 (15,16,49,50). To promote changes in vascular reactivity, remodeling, inflammation, and oxidative stress, ET-1 activates MAPK signaling pathways, including ERK1/2 (7,19,21,48).…”

Mediterranean diet, endothelial function and vascular inflammatory markers

“…A low production capacity of IL-10 has been found to be associated with the metabolic syndrome and type 2 diabetes 22 -24 . Experimental studies using gene-targeted mice 25 provide direct evidence that IL-10 offers some protection against endothelial dysfunction during diabetes and that this effect is mediated by inhibition of increased in superoxide anion in blood vessels. A reduced IL-10 serum level represents a marker of plaque instability favouring the development of acute coronary syndromes, and also indicative of a poor prognosis even after the occurrence of an acute ischaemic event caused by plaque instability 26 .…”

Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats

“…By contrast, hypertension inhibited IL-10 and HO-1 expression, with a resultant increase in ALT to a level higher than that caused by the CDAA diet alone. In addition, indirect evidence indicates that IL-10 exerts a protective effect on endothelial function in diabetes and hypertension (17,30). IL-10 has also been shown to inhibit the activation of hepatic stellate cells and decrease hepatic fibrosis and apoptosis in a CCl4-induced rat liver fibrosis model (31,28).…”