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

Background and Purpose-The role in blood vessels of interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is not known. Using mice with targete d deletion of the gene for IL-10 (IL-10(-/-)), we examined the hypothesis t hat IL-10 is a major modulator of the vascular effects of lipopolysaccharid e (LPS). Methods-We examined in vitro responses of carotid arteries obtained from wi ld-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 mg). Results-Contraction of the carotid artery in response to U46619 was impaire d in IL-10-deficient mice treated with LPS compared with LPS-treated contro ls. After LPS, U46619 (0.03 and 0.1 mu g/mL) contracted the carotid artery by 0.11 +/- 0.02 (mean +/- SEM) and 0.38 +/- 0.03 g in wild-type (n = 10) a nd 0.03 +/- 0.01 and 0.19 +/- 0.03 g in IL-10-deficient (n = 8) mice (P<0.0 5 versus control). Aminoguanidine, an inhibitor of inducible nitric oxide s ynthase (iNOS), had no significant effect on contraction of the carotid art ery from LPS-treated control mice but restored contraction of the carotid a rtery 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 grea ter impairment of contractile responses of the carotid artery in IL-10-defi cient mice than in control mice. Impaired contractile function was eliminat ed by aminoguanidine, suggesting that expression of iNOS is enhanced in art eries 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-t ype mice. RT-PCR products for iNOS were not present in arteries from vehicl e-treated animals (IL-10-deficient or wild-type mice). Conclusions-This is the first evidence that endogenous IL-10 is a major det erminant of the effects of LPS on vascular tone. The results suggest that i mpaired constrictor responses of the carotid artery after LPS in IL-10-defi cient mice are mediated by enhanced expression of iNOS.