LINOMIDE ADMINISTRATION TO MICE ATTENUATES THE INDUCTION OF NITRIC-OXIDE SYNTHASE ELICITED BY LIPOPOLYSACCHARIDE-ACTIVATED MACROPHAGES AND PREVENTS NEPHRITIS IN MRL MP-LPR/LPR MICE/

Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses, Local generation of high nitric oxide output through the expression of the calcium-independent, cytoki ne-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifi cally suppress iNOS expression or inhibit its activity may therefore p rovide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmun e disease. We show compelling evidence that linomide, an immunomodulat or known to ameliorate autoimmune diseases, prevents accumulation in t he macrophages of mRNA encoding iNOS in mice injected with LPS. This e ffect is partially mediated by the blocking of TNF-alpha and IL-beta p roduction by activated macrophages. Here, we also present evidence tha t kidneys from MRL/Mp-lpr/lpr mice express high iNOS levels when the m ice develop glomerulonephritis. The administration of linomide to MRL/ Mp-lpr/lpr mice significantly decreases iNOS mRNA levers and prevents the development of glomerulonephritis, extending the half-life of mice of this strain. This linomide effect is compatible with its role in p reventing the development of autoimmune disease and extends its possib le use to other pathologic manifestations associated with iNOS express ion, such as the systemic lupus erythematosus-associated glomeruloneph ritis present in MRL/Mp-lpr/lpr mice.