title: Cooperation of TLR2 with MyD88, PI3K, and Rac1 in lipoteichoic acid-induced cPLA2/COX-2-dependent airway inflammatory responses.
abstract: Lipoteichoic acid (LTA) plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. Cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin (IL)-6 have been demonstrated to engage in airway inflammation. In this study, LTA-induced cPLA(2) and COX-2 expression and PGE(2) or IL-6 synthesis were attenuated by transfection with siRNAs of TLR2, MyD88, Akt, p42, p38, JNK2, and p65 or pretreatment with the inhibitors of PI3K (LY294002), p38 (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin) in human tracheal smooth muscle cells (HTSMCs). LTA also induced cPLA(2) and COX-2 expression and leukocyte count in bronchoalveolar lavage fluid in mice. LTA-regulated PGE(2) or IL-6 production was inhibited by pretreatment with the inhibitors of cPLA(2) (AACOCF(3)) and COX-2 (NS-398) or transfection with cPLA(2) siRNA or COX-2 siRNA, respectively. LTA-stimulated NF-kappaB translocation or cPLA(2) phosphorylation was attenuated by pretreatment with LY294002, SB202190, U0126, or SP600125. Furthermore, LTA could stimulate TLR2, MyD88, PI3K, and Rac1 complex formation. We also demonstrated that Staphylococcus aureus could trigger these responses through a similar signaling cascade in HTSMCs. It was found that PGE(2) could directly stimulate IL-6 production in HTSMCs or leukocyte count in bronchoalveolar lavage fluid in mice. These results demonstrate that LTA-induced MAPKs activation is mediated through the TLR2/MyD88/PI3K/Rac1/Akt pathway, which in turn initiates the activation of NF-kappaB, and ultimately induces cPLA(2)/COX-2-dependent PGE(2) and IL-6 generation.
authors.affiliation: Department of Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: I-Ta
authors.initials: IT
authors.lastname: Lee
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Tung
authors.forename: Shyi-Wu
authors.initials: SW
authors.lastname: Wang
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Jwu-Ching
authors.initials: JC
authors.lastname: Shu
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism; D013682:Teichoic Acids / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D054513:Group IV Phospholipases A2; D020830:rac1 GTP-Binding Protein