MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components.
MD-2 is associated with Toll-like receptor 4 (TLR4) on the cell surface and enables TLR4 to respond to LPS. We tested whether MD-2 enhances or enables the responses of both TLR2 and TLR4 to Gram-negative and Gram-positive bacteria and their components. TLR2 without MD-2 did not efficiently respond to highly purified LPS and LPS partial structures. MD-2 enabled TLR2 to respond to nonactivating protein-free LPS, LPS mutants, or lipid A and enhanced TLR2-mediated responses to both Gram-negative and Gram-positive bacteria and their LPS, peptidoglycan, and lipoteichoic acid components. MD-2 enabled TLR4 to respond to a wide variety of LPS partial structures, Gram-negative bacteria, and Gram-positive lipoteichoic acid, but not to Gram-positive bacteria, peptidoglycan, and lipopeptide. MD-2 physically associated with TLR2, but this association was weaker than with TLR4. MD-2 enhanced expression of both TLR2 and TLR4, and TLR2 and TLR4 enhanced expression of MD-2. Thus, MD-2 enables both TLR4 and TLR2 to respond with high sensitivity to a broad range of LPS structures and to lipoteichoic acid, and, moreover, MD-2 enhances the responses of TLR2 to Gram-positive bacteria and peptidoglycan, to which the TLR4-MD-2 complex is unresponsive.
Dziarski
R
R
Northwest Center for Medical Education, Indiana University School of Medicine, Gary, IN 46408, USA. rdziar@iun.edu
Wang
Q
Q
Miyake
K
K
Kirschning
C J
CJ
Gupta
D
D
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002473:Cell Wall / Q000276:immunology*; D029721:Drosophila Proteins; D006090:Gram-Negative Bacteria / Q000276:immunology*; D006094:Gram-Positive Bacteria / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity; D008074:Lipoproteins / Q000276:immunology; D008213:Lymphocyte Activation; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010457:Peptidoglycan / Q000276:immunology; D011134:Polysaccharides / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012995:Solubility; D013682:Teichoic Acids / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D029721:Drosophila Proteins; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D008074:Lipoproteins; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D011134:Polysaccharides; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C009900:lipoteichoic acid