IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation.
Little is known about the role of interleukin-10 (IL-10), an anti-inflammatory cytokine, in blood vessels. We used IL-10-deficient mice (IL-10 -/-) to examine the hypothesis that IL-10 protects endothelial function after lipopolysaccharide (LPS) treatment. The responses of carotid arteries were studied in vitro 6 h after injection of a relatively low dose of LPS (10 microgram ip). In IL-10 -/- mice, the maximum relaxation to ACh (3 microM) was 56 +/- 6% (means +/- SE) after LPS injection and 84 +/- 4% after vehicle injection (P < 0.05). Thus endothelium-dependent relaxation was impaired in carotid arteries from IL-10 -/- mice after LPS injection. In contrast, this dose of LPS did not alter relaxation to ACh in vessels from wild-type (IL-10 +/+) mice. Relaxation to nitroprusside and papaverine was similar in arteries from both IL-10 -/- and IL-10 +/+ mice after vehicle or LPS injection. Because inflammation is associated with increased levels of reactive oxygen species, we also tested the hypothesis that superoxide contributes to the impairment of endothelial function by LPS in the absence of IL-10. Results using confocal microscopy and hydroethidine indicated that levels of superoxide are elevated in carotid arteries from IL-10 -/- mice compared with IL-10 +/+ mice after LPS injection. The impaired relaxation of arteries from IL-10 -/- mice after LPS injection was restored to normal by polyethylene glycol-suspended superoxide dismutase (50 U/ml) or allopurinol (1 mM), an inhibitor of xanthine oxidase. These data provide direct evidence that IL-10 protects endothelial function after an acute inflammatory stimulus by limiting local increases in superoxide. The source of superoxide in this model may be xanthine oxidase.
Gunnett
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CA
Department of Internal Medicine and Department of Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081, USA.
Heistad
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DD
Berg
D J
DJ
Faraci
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FM
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005456:Fluorescent Dyes; D016753:Interleukin-10 / Q000172:deficiency*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010617:Phenanthridines; D012016:Reference Values; D013481:Superoxides / Q000378:metabolism*; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D005456:Fluorescent Dyes; D008070:Lipopolysaccharides; D010617:Phenanthridines; D013481:Superoxides; D016753:Interleukin-10; C058428:hydroethidine