MODULATION OF LIPOPOLYSACCHARIDE-INDUCED CYTOKINE GENE-EXPRESSION IN MOUSE BONE MARROW-DERIVED MACROPHAGES BY MURAMYL DIPEPTIDE

Previous studies have shown that an i.v. injection of muramyl dipeptid e (MDP) before a LPS challenge strongly potentiated serum TNF and IL-6 release in mice. Therefore the direct action of MDP was examined on T NF-producing cells, namely in macrophages stimulated or not by LPS. Th e level of TNF-alpha, IL-1 alpha, and IL-6 mRNA was determined in bone marrow-derived macrophages (BMM). A marked TNF-alpha mRNA accumulatio n was found between 1 and 6 h after stimulation with MDP or LPS. LPS-i nduced IL-1 alpha mRNA transcripts were detected later (3 h) than thos e after MDP induction (1 h). Conversely, kinetic induction of the IL-6 mRNA transcript was delayed in MDP-treated BMM as compared with LPS-s timulated cells. MDP pretreatment of BMM for 3 h not only enhanced the total level of LPS-induced TNF-alpha, IL-1 alpha, and IL-6 mRNA (resp ectively 2.9-, 1.6-, and 2.4-fold increase), but it also delayed the k inetics of IL-1 alpha and IL-6 species accumulation. The enhancement i nduced by MDP pretreatment at the level of cytokine mRNA accumulation was correlated with an increase in LPS-induced TNF and IL-6 biologic a ctivity production in supernatant fluids. In addition, in BMM from C3H /HeJ mice MDP pretreatment enhanced the weak effect of LPS on TNF mRNA transcript accumulation and was required to produce LPS-induced TNF b ioactivity. Our results suggest that MDP and LPS could act through dis tinct pathway(s) to induce cytokine gene expression. Moreover, the pri ming effect displayed by MDP could result in a modulation of the LPS-i nduced cytokine gene expression at the transcriptional and/or post-tra nscriptional level.