The Role of Nitric Oxide in the Pathogenesis of Spontaneous Murine Autoimmune Disease: Increased Nitric Oxide Production and Nitric Oxide Synthase Expression in MRL-lpr/lpr Mice, and Reduction of Spontaneous Glomerulonephritis .and Arthritis by Orally Administered NG-Monomethyl-L-Arglnlne

MRL-I/r/I/r mice spontaneously develop various manifestations of autoimmunity indnding an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinfhmmatory actions, in the pathogenesis of MRL1/r/I/r autoimmune disease. MRL-I/r/I/r mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MILL-+/+ and B61/r/I/r congenic strains. In addition, MRL-I/r///r peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-I/r/I/r mice had increased expression of inducible nitric oxide synthase (NOS) mILNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NC-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-1/r/Ipr mice. By using interspecific backcross mice, the gene for inducible NOS (Nos~) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-I/r/l/r cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.