title: Lipoteichoic acid induces HO-1 expression via the TLR2/MyD88/c-Src/NADPH oxidase pathway and Nrf2 in human tracheal smooth muscle cells.
abstract: Heme oxygenase (HO)-1 is a stress-inducible rate-limiting enzyme in heme degradation that confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system-stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. We report that LTA is an inducer of HO-1 expression mediated through the signaling pathways in human tracheal smooth muscle cells (HTSMCs). LTA-induced HO-1 protein levels, mRNA expression, and promoter activity were attenuated by transfection with dominant negative mutants of TLR2 and MyD88, by pretreatment with the inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride (DPI) and apocynin (APO)), and reactive oxygen species (ROS) scavenger (N-acetyl-l-cysteine) or by transfection with small interfering RNAs of Src and NF-E2-related factor 2 (Nrf2). LTA-stimulated translocation of p47(phox) and Nrf2 or ROS production was attenuated by transfection with dominant negative mutants of TLR2, MyD88, and c-Src and by pretreatment with DPI or APO. Furthermore, LTA-induced TLR2, MyD88, TNFR-associated factor (TRAF)6, c-Src, and p47(phox) complex formation was revealed by immunoprecipitation using an anti-TLR2 or anti-c-Src Ab followed by Western blot analysis against an anti-TLR2, anti-MyD88, anti-TRAF6, anti-c-Src, or anti-p47(phox) Ab. These results demonstrated that LTA-induced ROS generation was mediated through the TLR2/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO-1 expression in HTSMCs.
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: I-Ta
authors.initials: IT
authors.lastname: Lee
authors.forename: Shyi-Wu
authors.initials: SW
authors.lastname: Wang
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Shue-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008070:Lipopolysaccharides / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014132:Trachea / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human