IL-4 plays a crucial role in regulating oxidative damage in the liver during schistosomiasis.
Liver enlargement and hepatocyte proliferation, normal responses in wild-type (WT) mice infected with the parasitic helminth Schistosoma mansoni, were found to be severely impaired in infected IL-4(-/-) mice. Compared with WT mice, increased levels of O(2)(-), NO, and the more highly reactive ONOO(-) were detected in the liver and produced by lesional cells isolated from liver granulomas of infected IL-4(-/-) mice. Concurrently, antioxidant defenses in the liver, specifically catalase levels, diminished dramatically during the course of infection in these animals. This contrasted to the situation in infected WT mice, where catalase levels remained as high as those in normal mice. Actual levels of reactive oxygen and nitrogen intermediates in the livers of infected IL-4(-/-) animals are thus likely to be considerably higher than those in the livers of infected WT mice. To determine whether these changes contributed to the development of the more severe disease that characterizes infection in the IL-4(-/-) animals, we treated infected IL-4(-/-) mice with uric acid, a potent scavenger of ONOO(-). This resulted in significantly increased hepatocyte proliferation, decreased morbidity, and prolonged survival. Taken together, these data indicate that IL-4 is playing a protective role during schistosomiasis by controlling the tight regulation of the generation of reactive oxygen and nitrogen intermediates in the liver.
La Flamme
A C
AC
Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
Patton
E A
EA
Bauman
B
B
Pearce
E J
EJ
D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D002374:Catalase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D005260:Female; D006099:Granuloma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D014527:Uric Acid / Q000008:administration & dosage
D000975:Antioxidants; D017382:Reactive Oxygen Species; D015847:Interleukin-4; D014527:Uric Acid; D009569:Nitric Oxide; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009584:Nitrogen