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, Phillip Ruiz, Audrey A. Alexander, Mary A. Misukonis, David S. Pisetsky, J. Brice Weinberg

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

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Nitric Oxide Synthase Type II
Autoimmune Diseases
Nitric Oxide
Vasculitis
Kidney
Rheumatoid Factor
Homologous Recombination
Antinuclear Antibodies
Peritoneal Macrophages
Glomerulonephritis
Nitric Oxide Synthase
Arthritis
Arginine

ASJC Scopus subject areas

  • Immunology

Cite this

Gilkeson, G. S., Mudgett, J. S., Seldin, M. F., Ruiz, P., Alexander, A. A., Misukonis, M. A., ... 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

Clinical and serologic manifestations of autoimmune disease in MRL- lpr/lpr mice lacking nitric oxide synthase type 2. / Gilkeson, Gary S.; Mudgett, John S.; Seldin, Michael F.; Ruiz, Phillip; Alexander, Audrey A.; Misukonis, Mary A.; Pisetsky, David S.; Weinberg, J. Brice.

In: Journal of Experimental Medicine, Vol. 186, No. 3, 04.08.1997, p. 365-373.

Research output: Contribution to journalArticle

Gilkeson, GS, Mudgett, JS, Seldin, MF, Ruiz, P, Alexander, AA, Misukonis, MA, Pisetsky, DS & Weinberg, JB 1997, 'Clinical and serologic manifestations of autoimmune disease in MRL- lpr/lpr mice lacking nitric oxide synthase type 2', Journal of Experimental Medicine, vol. 186, no. 3, pp. 365-373. https://doi.org/10.1084/jem.186.3.365
Gilkeson, Gary S. ; Mudgett, John S. ; Seldin, Michael F. ; Ruiz, Phillip ; Alexander, Audrey A. ; Misukonis, Mary A. ; Pisetsky, David S. ; Weinberg, J. Brice. / Clinical and serologic manifestations of autoimmune disease in MRL- lpr/lpr mice lacking nitric oxide synthase type 2. In: Journal of Experimental Medicine. 1997 ; Vol. 186, No. 3. pp. 365-373.
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