Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes.
MD-2 is associated with TLR4 on the cell surface and enables TLR4 to respond to LPS. TLR2 without MD-2 does not respond to pure protein-free endotoxic LPS, ReLPS, and lipid A. MD-2 enables TLR2 to respond to non-activating LPS, ReLPS, and lipid A, and enhances TLR2-mediated responses to Gram-negative and Gram-positive bacteria, protein-containing LPS, peptidoglycan, and lipoteichoic acid. MD-2 enables TLR4 to respond to a wide variety of endotoxic LPS partial structures, Gram-negative bacteria, and Gram-positive lipoteichoic acid, but not to Gram-positive bacteria, peptidoglycan, and lipopeptide. MD-2 physically associates with both TLR4 and TLR2, but the association with TLR2 is weaker than with TLR4. Also, MD-2 and TLR2 and TLR4 enhance each other's expression. The highest induced genes in human monocytes stimulated with Gram-positive and Gram-negative bacterial cell wall components are chemokine genes, and IL-8 is the highest induced chemokine. Both Gram-positive and Gram-negative bacteria activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-->kappaB signal transduction pathway that induces transcription of the IL-8 gene. Therefore, TLR2 is a functional receptor for both Gram-positive and Gram-negative bacteria and it induces activation of IL-8.
Dziarski
R
R
Northwest Center for Medical Education, Indiana University School of Medicine, Gary, Indiana, USA. rdziar@iun.edu
Gupta
D
D
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology*; D018925:Chemokines / Q000235:genetics*; D029721:Drosophila Proteins; D005786:Gene Expression Regulation; D006090:Gram-Negative Bacteria / Q000276:immunology*; D006094:Gram-Positive Bacteria / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D000954:Antigens, Surface; D018925:Chemokines; D029721:Drosophila Proteins; D016209:Interleukin-8; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors