Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2.
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 NG-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.
Gilkeson
G S
GS
Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston 29425, USA.
Mudgett
J S
JS
Seldin
M F
MF
Ruiz
P
P
Alexander
A A
AA
Misukonis
M A
MA
Pisetsky
D S
DS
Weinberg
J B
JB
D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000473:pathology; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology / Q000473:pathology; D015151:Immunoblotting; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000201:enzymology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D013154:Spleen / Q000201:enzymology / Q000473:pathology
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase