The effects of NO synthase inhibitors on murine collagen-induced arthritis do not support a role of NO in the protective effect of IFN-gamma.
DBA/1 mice deficient in expressing the interferon-gamma (IFN-gamma) membrane receptor (IFN-gammaR KO mice) are more susceptible to collagen-induced arthritis (CIA) than wild-type mice, indicating that endogenous IFN-gamma plays a protective role in the pathogenesis of CIA. In IFN-gammaR KO mice, nitric oxide (NO) production during CIA is impaired. Because NO is known to exert immunosuppressive and anti-inflammatory effects in certain model systems, the protective effect of IFN-gamma might be mediated by NO. Here, we tested in wild-type mice whether inhibition of NO production by metabolic inhibitors, aminoguanidine (AG) and L-N-(1-iminoethyl)lysine (L-NIL), could mimic the ablation of the IFN-gamma receptor. A high-dose regimen of AG supplied in the drinking water inhibited NO production, disease development, and anticollagen antibody production but was also associated with transient body weight loss. At a dose and time regimen that still inhibited NO production but did not cause body weight loss, AG failed to affect disease scores. Treatment with L-NIL, which more specifically than AG affects inducible NO production, caused a slight increase in anticollagen antibody production although not significantly affecting disease occurrence. These data indicate that the diminished capacity of the IFN-gammaR KO mice to produce NO following immunization with collagen is unlikely to account for their higher susceptibility to CIA.
Laboratory of Immunobiology, Rega Institute, University of Leuven, Faculty of Medicine, Belgium.
K
K
Vermeire
L
L
Thielemans
P
P
Matthys
A
A
Billiau
D000284:Administration, Oral; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D003094:Collagen / Q000276:immunology / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D020022:Genetic Predisposition to Disease; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000502:physiology*; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D017471:Receptors, Interferon / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects; D000096743:Interferon gamma Receptor
D001323:Autoantibodies; D003094:Collagen; D004791:Enzyme Inhibitors; D006146:Guanidines; D007371:Interferon-gamma; D008239:Lysine; D009566:Nitrates; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C090663:N(6)-(1-iminoethyl)lysine; C496317:Nos2 protein, mouse; C004479:pimagedine