Muramyl dipeptide potentiates the ability of lipoteichoic acid to induce cyclooxygenase-2 expression in murine macrophages (157.11)

Abstract

Abstract Gram-positive bacterial cell wall contains lipoteichoic acid (LTA) and thick peptidoglycan (PGN) layers, both of which are the major virulence factors containing proinflammatory potential. In order to examine if LTA together with PGN synergistically induces inflammatory responses, we investigated the ability of staphylococcal LTA to induce cyclooxygenase-2 (COX-2) expression in the presence of muramyl dipeptide (MDP), the minimal structural unit of PGN with inflammatory potential, in murine macrophages. Although MDP failed to induce COX-2 expression, LTA alone was able to induce COX-2 expression and MDP remarkably enhanced LTA-induced COX-2 expression at both protein and mRNA levels. Up-regulation was also observed in the production of prostaglandin E2, which is mediated by COX-2. Notably, COX-2 expression, induced by LTA plus MDP treatment, was down-regulated by inhibitors for MAP kinases (ERK, p38 and JNK/SAPK), PI3 kinases, and reactive oxygen species, but not by inhibitors for PKC or PKA. Transient transfection and luciferase reporter gene assays demonstrated that MDP also enhanced the LTA-induced activation of transcription factors, NF-κB, CRE and AP-1, all of which are involved in the transcriptional activity of COX-2. Conclusively, these results suggest that MDP potentiates LTA-induced inflammatory responses by enhancing the expression of COX-2 in macrophages.