Muramyl dipeptide potentiates lipoteichoic acid-induced nitric oxide production in macrophage (135.32)

Abstract

Abstract Pathogen-associated molecular patterns, such as lipoteichoic acid (LTA) and peptidoglycan (PGN) of gram-positive bacteria, often cooperate together to induce immune responses in the host. In this study, we investigated nitric oxide (NO) production by macrophages in response to LTA and muramyl dipeptide (MDP), a minimal structural unit of PGN. MDP alone could not induce NO production in both murine macrophages and a murine macrophage-like cell line, RAW 264.7, whereas LTA induced NO production. However, MDP potentiated LTA-induced NO production under the same condition. This was due to enhanced activation of Toll-like receptor 2 (TLR2) recognizing LTA since MDP increased TLR2 expression on the surface of macrophages and the potentiation effect was abolished in the macrophages derived from TLR2-deficient mice. Furthermore, MyD88 and MAP kinases such as ERK and p38 kinase also appear to be essentially required for such potentiation, which was determined by using MyD88-deficient macrophages and their specific inhibitors, PD98059 and SB203580, respectively. Subsequently, MDP enhanced the LTA-induced activation of NF-κB in RAW 264.7. These findings suggest that MDP potentiates the ability of LTA to stimulate macrophages via upregulating TLR2 activity. Supported by a grant from 21C Frontier Microbial Genomics and Application Center Program, Ministry of Science and Technology (11-2008-15-005-01).