Preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2-and MyD88-dependent signaling pathway

Mycoplasmas and their membranes are potent activators of macrophages, the a ctive principle being Lipoproteins and lipopeptides. Two stereoisomers of t he mycoplasmal lipopeptide macrophage-activating lipopeptide-2 (MALP-2) dif fering in the configuration of the lipid moiety were synthesized and compar ed in their macrophage-activating potential, the R-MALP being >100 times mo re active than the S-MALP in stimulating the release of cytokines, chemokin es, and NO, To assess the role of the Toll-like receptor (TLR) family in my coplasmal lipopeptide signaling, the MALP-2-mediated responses were analyze d using macrophages from wild-type, TLR2-, TLR4-, and MyD88-deficient mice, TLR2- and MyD88-deficient cells showed severely impaired cytokine producti ons in response to R- and S-MALP, The MALP-induced activation of intracellu lar signaling molecules was fully dependent on both TLR2 and MyD88. There w as a strong preference for the R-MALP in the recognition by its functional receptor, TLR2.