title: Upregulation of MUC5AC gene expression by IL-4 through CREB in human airway epithelial cells.
abstract: Mucus hypersecretion is an important characteristic feature of the pathogenesis of allergy. Although interleukin (IL)-4 is known to be an inflammatory mediator in respiratory diseases, the mechanism by which IL-4 induces MUC5AC gene expression has not been fully explored. The aim of this study was to investigate the mechanism by which IL-4 induces MUC5AC gene expression in the airway. We examined the role of mitogen-activated protein kinase (MAPK) signaling on MUC5AC gene expression in airway epithelium. We showed that phosphorylation of ERK1/2 increased after treatment of cells with IL-4, whereas phosphorylation of p38 and JNK was not detected. In addition, pharmacologic and genetic inhibition of ERK1/2 abolished IL-4-induced MUC5AC gene expression. Moreover, we investigated the activation of p90 ribosomal S6 kinase 1 (RSK1) as a downstream signaling target of ERK1/2 in IL-4 signaling. The activation of RSK1 was prevented by pretreatment with PD98059 or plasmid expressing a MEK1 dominant-negative mutant. We also found that RSK1 mediated the IL-4-induced phosphorylation of cAMP response element-binding protein (CREB) and the transcription of MUC5AC. Furthermore, the cAMP-response element (CRE) in the MUC5AC promoter appears to be important for IL-4-induced MUC5AC gene expression in NCI-H292 cells.
authors.affiliation: Department of Pediatrics, College of Medicine, Kwandong University, Koyang, Korea.
authors.forename: Cheol Hong
authors.initials: CH
authors.lastname: Kim
authors.forename: Kyu-Earn
authors.initials: KE
authors.lastname: Kim
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Kyoung Seob
authors.initials: KS
authors.lastname: Song
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D055271:Mucin 5AC / Q000096:biosynthesis*; D010766:Phosphorylation; D020218:Response Elements / Q000235:genetics; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D055271:Mucin 5AC; D015847:Interleukin-4; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one