Synergism Between Interleukin (IL)-17 and Toll-like Receptor 2 and 4 Signals to Induce IL-8 Expression in Cystic Fibrosis Airway Epithelial Cells

Journal of Pharmacological Sciences

Hirofumi Kai³  Kouhei Onuki³  Mary Ann Suico³  Shota Mizunoe³  Tsuyoshi Shuto³  Chizuru Matsumoto³  Keiko Ueno-Shuto¹  Kenji Watanabe³  Shingo Suzuki³  Dieter C. Gruenert² 

[1]Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, Japan

[2]Departments of Otolaryngology - Head and Neck Surgery and Laboratory Medicine, University of California, San Francisco, USA

[3]Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE “Cell Fate Regulation Research and Education Unit”, Kumamoto University, Japan

关键词: interleukin (IL)-17;    toll-like receptor 2 and 4 (TLR2/TLR4);    IL-8;    cystic fibrosis (CF);    p38;   

DOI  :  10.1254/jphs.11240FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(39)Cited-By(8)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.

【 授权许可】

Unknown