Muramyl dipeptide potentiates cytokine-induced activation of inducible nitric oxide synthase in rat astrocytes

We investigated the influence of muramyl dipeptide (MDP), a cell wall compo nent of Gram-positive bacteria, on cytokine-induced nitric oxide (NO) produ ction in rat primary astrocytes. MDP alone did not induce NO release in ast rocyte cultures. However, MDP increased astrocyte NO production and subsequ ent nitrite accumulation triggered by IFN-gamma. IFN-gamma -activated expre ssion of mRNA for inducible NO synthase (iNOS) and iNOS transcription facto r interferon regulatory factor-1 (IRF-1) was markedly enhanced in astrocyte s treated with MDP. The potentiating effect of MDP on IFN-gamma -induced NO production in astrocytes was completely blocked with protein tyrosine kina se (PTK) inhibitor genistein or mitogen activated protein kinase (MAPK) inh ibitor PD98059. In contrast, protein kinase C (PKC) inhibitor calphostin C did not affect ability of MDP to augment IFN-gamma -triggered astrocyte NO synthesis. These results suggest that MDP synergizes with IFN-gamma in the induction of iNOS gene in astrocytes through mechanisms involving PTK and M APK, but not PKC activation. Finally, MDP also augmented NO production and iNOS mRNA expression in astrocytes treated with IL-1 beta. (C) 2000 Elsevie r Science B.V. All rights reserved.