J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/08/365/09 $2.00
Volume 186, Number 3, August 4, 1997 365-373

Clinical and Serologic Manifestations of Autoimmune Disease in MRL-lpr/lpr Mice Lacking Nitric Oxide Synthase Type 2 

By Gary S. Gilkeson,^* John S. Mudgett, Michael F. Seldin,^§ Phil Ruiz, Audrey A. Alexander,^¶ Mary A. Misukonis,^¶ David S. Pisetsky,^¶ and J. Brice Weinberg^¶

^* From the Ralph H. Johnson Veterans Affairs Medical Center and the Medical University of South Carolina, Charleston, South Carolina 29425;  Merck Research Laboratories, Rahway, New Jersey 07065; ^§ University of California Davis, Davis, California 95616;  University of Miami Medical Center, Miami, Florida 33136; and the ^¶ Veterans Affairs and Duke University Medical Centers, Durham, North Carolina 27705

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 wildtype (+/+) 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.

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