Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8.
This study was done to elucidate the signal transduction pathway of interleukin-8 (IL-8) induction by gram-positive bacteria. Bacteria (micrococci) and peptidoglycan (PGN) induced transcription of IL-8 in HEK293 cells expressing Toll-like receptor 2 (TLR2) and CD14 but not in those expressing TLR1 or TLR4. A mutation within the NF-kappaB site in the IL-8 promoter abrogated transcriptional induction of IL-8 by the two stimulants. Dominant negative myeloid differentiation protein (MyD88), IL-1 receptor-associated kinase (IRAK), NFkappaB-inducing kinase (NIK), and IkappaB kinase (IKK) mutant forms completely inhibited micrococcus- and PGN-induced activation of NF-kappaB and expression of the gene for IL-8. Induction of NF-kappaB was partially inhibited by dominant negative tumor necrosis factor receptor-associated kinase 6 (TRAF6) but not TRAF2, whereas induction of IL-8 gene was partially inhibited by both TRAF6 and TRAF2. These data indicate that micrococci and PGN induce TLR2-dependent activation of the gene for IL-8 and that this activation requires MyD88, IRAK, NIK, IKK, and NF-kappaB and may also utilize TRAF6 and, to a lesser extent, TRAF2.
Northwest Center for Medical Education, Indiana University School of Medicine, Gary, Indiana 46408, USA.
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Wang
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Dziarski
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Kirschning
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Muzio
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Gupta
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000502:physiology*; D002460:Cell Line; D029721:Drosophila Proteins; D006801:Humans; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D016209:Interleukin-8 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000502:physiology*; D008837:Micrococcus / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000502:physiology*; D010457:Peptidoglycan / Q000494:pharmacology*; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010457:Peptidoglycan; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000097782:NF-kappaB-Inducing Kinase; C507779:MYD88 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human