title: Involvement of MAPKs and NF-kappaB in LPS-induced VCAM-1 expression in human tracheal smooth muscle cells.
abstract: Lipopolysaccharide (LPS) has been shown to induce the expression of adhesion molecules on airway epithelial and smooth cells and contributes to inflammatory responses. Here, the roles of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) pathways for LPS-induced vascular cell adhesion molecule (VCAM)-1 expression were investigated in HTSMCs. LPS-induced expression of VCAM-1 protein and mRNA in a time-dependent manner, was significantly inhibited by inhibitors of MEK1/2 (U0126), p38 (SB202190), and c-Jun-N-terminal kinase (JNK; SP600125). The involvement of p42/p44 MAPK and p38 in these responses was further confirmed by that transfection with small interference RNAs (siRNA) direct against MEK, p42, and p38 significantly attenuated LPS-induced VCAM-1 expression. Consistently, LPS-stimulated phosphorylation of p42/p44 MAPK and p38 was attenuated by pretreatment with U0126 or SB202190, and transfection with these siRNAs, respectively. In addition, LPS-induced VCAM-1 expression was significantly blocked by a specific NF-kappaB inhibitor helenalin. LPS-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha was blocked by helenalin, U0126, SB202190, or SP600125. Moreover, the resultant enhancement of VCAM-1 expression increased the adhesion of polymorphonuclear cells to monolayer of HTSMCs which was blocked by pretreatment with helenalin, U0126, or SP600125 prior to LPS exposure. Taken together, these results suggest that in HTSMCs, activation of p42/p44 MAPK, p38, and JNK pathways, at least in part, mediated through NF-kappaB, is essential for LPS-induced VCAM-1 gene expression. These results provide new insight into the mechanisms of LPS action that bacterial toxins may promote inflammatory responses in the airway disease.
authors.affiliation: Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Lin
authors.forename: Shue-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Wang
authors.forename: Jong-Shyan
authors.initials: JS
authors.lastname: Wang
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases