Interleukin-10 (IL-10) is an anti-inflammatory cytokine with protective actions on the vasculature. On the other hand, endothelin-1 (ET-1) has potent vasoconstrictor, mitogenic, and pro-inflammatory activities, which have been implicated in the pathophysiology of a number of cardiovascular diseases. We hypothesized that in a condition where ET-1 expression is upregulated, as upon infusion of tumor necrosis factor-alpha (TNF-), IL-10 confers vascular protection to ET-1-induced injury. Aortic rings and first-order mesenteric arteries from male C57BL/6 (WT) and IL-10 knockout (IL^-10-/-) mice treated with human recombinant TNF- (220ng.kg^-1.day) or vehicle (saline) for 14 days were used. TNF-infusion significantly increased blood pressure in IL-10^-/-, but not WT mice. TNF-augmented vascular ET-1 mRNA expression in arteries from WT and IL-10^-/- mice. ETA receptor expression was increased in arteries from IL-10^-/- mice and TNF- infusion did not change vascular ETA receptor expression.either in control or IL-10^-/- mice. Both aorta and mesenteric arteries from IL-10^-/- mice infused with TNF- displayed increased contractile responses to ET-1, but not to the ETB receptor agonist, IRL-1620. The ETA receptor antagonist atrasentan completely abolished responses to ET-1 in aorta and mesenteric vessels, whereas the extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD-98059 abrogated increased contractions to ET-1 in arteries from IL-10^-/- mice infused with TNF-. Infusion of TNF- as well as knock down of IL-10 (IL-10^-/-) induced an increase in the total and phosphorylated forms of ERK1/2. These data demonstrate that IL-10 counteracts both ETA-mediated vascular responses to ET-1 as well as activation of ERK1/2-pathway.