Antiinflammatory properties of mycophenolate mofetil in murine endotoxemia: inhibition of TNF-alpha and upregulation of IL-10 release

Mycophenolate mofetil (MMF) is a new immunosuppressive agent currently used in organ transplantation and under evaluation in immune-mediated inflammat ory disorders such as rheumatoid arthritis. Although MMF was shown to inhib it purine nucleotide synthesis in lymphocytes, it is still unclear whether it might also exert direct antiinflammatory actions in vivo. To address thi s question, we evaluated the effects of MMF administration on the responses of mice to a single challenge with bacterial lipopolysaccharide (LPS). We observed that MMF treatment inhibits the release of tumor necrosis factor-a lpha (TNF-alpha) and nitric oxide (NO) upon LPS injection whereas it promot es IL-IO production. In parallel, MMF was found to protect mice from LPS-in duced lethality. Inhibition of TNF-a release was also observed in IL-10-def icient mice indicating that it does not exclusively depend on the upregulat ion of IL-10 endogenous synthesis. In view of the differential effects of M MF on the LPS-induced production of TNF-alpha and NO on one hand and that o f IL-IO on the other hand, we conclude that beside its immunosuppressive ac tion at the lymphocyte level, MMF is also endowed with antiinflammatory pro perties. (C) 1999 Published by Elsevier Science Ltd on behalf of the Intern ational Society for Immunopharmacology. All rights reserved.