Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice.
Nitric oxide (.NO) may exhibit proinflammatory features. .NO synthase type 2 (NOS2) is overexpressed and .NO overproduced in rodent models of induced inflammation. Blockage of .NO production by administration of NOS inhibitors prevents or reduces various types of induced inflammation in mice and rats. We have shown that autoimmune MRL-lpr/lpr mice overexpress NOS2 and overproduce .NO in an age-dependent fashion that parallels expression of arthritis, glomerulonephritis, and vasculitis. Blocking .NO production by oral administration of the NOS inhibitor NG-monomethyl-L-arginine reduced the arthritis, glomerulonephritis, and vasculitis, but it did not modify serum anti-DNA antibody levels or glomerular deposition of immune complexes. When mice with genetically disrupted NOS2 were backcrossed to MRL-lpr/lpr mice, the resultant (-/-) mice expressed no NOS2 and produced no .NO, the wild-type (+/+) mice overexpressed NOS2 and overproduced .NO (in comparison to normal, control mice), and the heterozygous (+/-) mice expressed and produced intermediate levels. Nephritis and arthritis in the (-/-) mice were comparable to that in MRL-lpr/lpr mice, but vasculitis was markedly decreased. Levels of anti-DNA antibodies were comparable in all mice, but IgG rheumatoid factor production was markedly reduced in the (-/-) mice. These results of studies in MRL-lpr/lpr mice with genetically disrupted NOS2 highlight the heterogeneity and complexity of the role of NOS2 and .NO in inflammation.
Weinberg
J B
JB
Department of Medicine, Veterans Affairs, Durham, North Carolina 27705, USA. brice@acpub.duke.edu
D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D051381:Rats
D018836:Inflammation Mediators; D009566:Nitrates; C039642:peroxynitric acid; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat