Clinical and serologic manifestations of autoimmune disease in MRL- lpr/lpr mice lacking nitric oxide synthase type 2

Gary S. Gilkeson, John S. Mudgett, Michael F. Seldin, Phil Ruiz, Audrey A. Alexander, Mary A. Misukonis, David S. Pisetsky, J. Brice Weinberg

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90 Scopus citations

Abstract

Nitric oxide (NO) is an important mediator of the inflammatory response. MRL-lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL-lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL-lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL-lpr/lpr mice to the N4 generation. MRL-lpr/lpr littermates homozygous for disrupted NOS2 (-/-), heterozygous for disrupted NOS2 (+/-), or wild-type (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL- lpr/lpr (-/-) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/-) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (-/-) animals, whereas that of (+/+) was high and (+/-) intermediate. The (-/-) mice developed glomerular and synovial pathology similar to that of the (+/-) and (+/+) mice. However, (-/-) mice and (+/-) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (- /-) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.

Original languageEnglish (US)
Pages (from-to)365-373
Number of pages9
JournalJournal of Experimental Medicine
Volume186
Issue number3
DOIs
StatePublished - Aug 4 1997

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Gilkeson, G. S., Mudgett, J. S., Seldin, M. F., Ruiz, P., Alexander, A. A., Misukonis, M. A., Pisetsky, D. S., & Weinberg, J. B. (1997). Clinical and serologic manifestations of autoimmune disease in MRL- lpr/lpr mice lacking nitric oxide synthase type 2. Journal of Experimental Medicine, 186(3), 365-373. https://doi.org/10.1084/jem.186.3.365