title: Synergism between interleukin (IL)-17 and Toll-like receptor 2 and 4 signals to induce IL-8 expression in cystic fibrosis airway epithelial cells.
abstract: Cystic fibrosis (CF) is the most common lethal inherited disorder and is caused by mutations in the gene encoding the CF transmembrane regulator (CFTR). The CF lung expresses a profound proinflammatory phenotype that appears to be related to a constitutive hypersecretion of interleukin (IL)-8 from airway epithelial cells in response to microbial infection. Since overproduction of IL-8 in CF contributes to massive bronchial infiltrates of neutrophils, identification of the pathways underlying IL-8 induction could provide novel drug targets for treatment of neutrophil-dominated inflammatory diseases such as CF. Here, we show that IL-17A synergistically increases IL-8 production induced by a toll-like receptor (TLR) 2 agonist, peptidoglycan (PGN), or TLR4 agonist, lipopolysaccharide (LPS), in a human CF bronchial epithelial cell line (CFBE41o-). A strong synergism was also observed in primary human CF bronchial epithelial cells, but not in human non-CF cell lines and primary cells. Notably, despite the induction of nuclear factor-κB and MAP kinases during TLR2 or TLR4 activation in CFBE41o-, IL-17A-dependent synergism appears to be the result of enhanced PGN- or LPS-induced phosphorylation of p38. Taken together, these studies provide evidence that IL-17A is a critical factor in increasing IL-8 expression in bacteria-infected CF airways via a pathway that regulates p38 phosphorylation.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.|The Japan Society for the Promotion of Science (JSPS), Tokyo 102-8472, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Mizunoe
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.|The Japan Society for the Promotion of Science (JSPS), Tokyo 102-8472, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ueno-Shuto
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.|The Japan Society for the Promotion of Science (JSPS), Tokyo 102-8472, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Onuki
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery.|Department of Laboratory Medicine.|Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research.|Helen Diller Family Comprehensive Cancer Center.|Institute for Human Genetics.|Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94115, USA.|Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Dieter C
authors.initials: DC
authors.lastname: Gruenert
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology*
chemical_list: D020381:Interleukin-17; D016209:Interleukin-8; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4