Cutting Edge: 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

• Published in: The Journal of immunology (1950) 2000-01, Vol.164 (2), p.554-557
• Main Authors: Takeuchi, Osamu, Kaufmann, Andreas, Grote, Karsten, Kawai, Taro, Hoshino, Katsuaki, Morr, Michael, Muhlradt, Peter F, Akira, Shizuo
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - physiology; Cells, Cultured; Drosophila Proteins; Lipopeptides; Lipoproteins - chemistry; Lipoproteins - physiology; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages, Peritoneal - immunology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mycoplasma fermentans - immunology; Myeloid Differentiation Factor 88; Oligopeptides - chemistry; Oligopeptides - physiology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Receptors, Immunologic; Signal Transduction - genetics; Signal Transduction - immunology; Stereoisomerism; Structure-Activity Relationship; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.2.554

Mycoplasmas and their membranes are potent activators of macrophages, the active principle being lipoproteins and lipopeptides. Two stereoisomers of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 (MALP-2) differing in the configuration of the lipid moiety were synthesized and compared in their macrophage-activating potential, the R-MALP being >100 times more active than the S-MALP in stimulating the release of cytokines, chemokines, and NO. To assess the role of the Toll-like receptor (TLR) family in mycoplasmal lipopeptide signaling, the MALP-2-mediated responses were analyzed using macrophages from wild-type, TLR2-, TLR4-, and MyD88-deficient mice. TLR2- and MyD88-deficient cells showed severely impaired cytokine productions in response to R- and S-MALP. The MALP-induced activation of intracellular signaling molecules was fully dependent on both TLR2 and MyD88. There was a strong preference for the R-MALP in the recognition by its functional receptor, TLR2.