Vascular effects of lipopolysaccharide are enhanced in interleukin-10-deficient mice.

Abstract

The role in blood vessels of interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is not known. Using mice with targeted deletion of the gene for IL-10 (IL-10(-/-)), we examined the hypothesis that IL-10 is a major modulator of the vascular effects of lipopolysaccharide (LPS). Methods-We examined in vitro responses of carotid arteries obtained from wild-type (129/SvEv or C57BL/6; IL-10(+/+)) and IL-10-deficient mice 6 hours after injection of a relatively low dose of LPS (10 microgram). Contraction of the carotid artery in response to U46619 was impaired in IL-10-deficient mice treated with LPS compared with LPS-treated controls. After LPS, U46619 (0.03 and 0.1 microgram/mL) contracted the carotid artery by 0.11+/-0.02 (mean+/-SEM) and 0.38+/-0.03 g in wild-type (n=10) and 0.03+/-0.01 and 0.19+/-0.03 g in IL-10-deficient (n=8) mice (P<0.05 versus control). Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), had no significant effect on contraction of the carotid artery from LPS-treated control mice but restored contraction of the carotid artery in response to U46619 in IL-10-deficient mice to levels seen in wild-type mice. Similar findings were obtained when phenylephrine was used as a vasoconstricting agent. These findings indicate that LPS produces much greater impairment of contractile responses of the carotid artery in IL-10-deficient mice than in control mice. Impaired contractile function was eliminated by aminoguanidine, suggesting that expression of iNOS is enhanced in arteries from IL-10-deficient mice. In carotid arteries from animals injected with LPS, reverse transcription-polymerase chain reaction (RT-PCR) products for iNOS were found more frequently in IL-10-deficient mice than in wild-type mice. RT-PCR products for iNOS were not present in arteries from vehicle-treated animals (IL-10-deficient or wild-type mice). This is the first evidence that endogenous IL-10 is a major determinant of the effects of LPS on vascular tone. The results suggest that impaired constrictor responses of the carotid artery after LPS in IL-10-deficient mice are mediated by enhanced expression of iNOS.