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.
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.
Takeuchi
O
O
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan.
Kaufmann
A
A
Grote
K
K
Kawai
T
T
Hoshino
K
K
Morr
M
M
Mühlradt
P F
PF
Akira
S
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D029721:Drosophila Proteins; D055666:Lipopeptides; D008074:Lipoproteins / Q000737:chemistry / Q000502:physiology*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016858:Mycoplasma fermentans / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides / Q000737:chemistry / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D055666:Lipopeptides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C106335:macrophage stimulatory lipopeptide 2