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.
Vermeire
K
K
Laboratory of Immunobiology, Rega Institute, University of Leuven, Faculty of Medicine, Belgium.
Thielemans
L
L
Matthys
P
P
Billiau
A
A
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