Cigarette Smoke Extract Enhances IL-17AInduced IL-8 Production via Up-Regulation of IL-17R in Human Bronchial Epithelial Cells
Kyoung-Hee Lee1,3, Chang-Hoon Lee1,2,3, Jisu Woo1, Jiyeong Jeong1, An-Hee Jang1, and Chul-Gyu Yoo1,2,* 
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea, 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea, 3These authors contributed equally to this work.
Received July 12, 2017; Revised December 6, 2017; Accepted January 10, 2018.; Published online February 21, 2018.
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Interleukin-17A (IL-17A) is a pro-inflammatory cytokine mainly derived from T helper 17 cells and is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) has been considered as a primary risk factor of COPD. However, the interaction between CS and IL-17A and the underlying molecular mechanisms have not been clarified. In the current study, we investigated the effects of cigarette smoke extract (CSE) on IL-17Ainduced IL-8 production in human bronchial epithelial cells, and sought to identify the underlying molecular mechanisms. IL-8 production was significantly enhanced following treatment with both IL-17A and CSE, while treatment with either IL-17A or CSE alone caused only a slight increase in IL-8 production. CSE increased the transcription of IL-17RA/RC and surface membrane expression of IL-17R, which was suppressed by an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway (LY294002). CSE caused inactivation of glycogen synthase kinase-3β (GSK-3β) via the PI3K/Akt pathway. Blockade of GSK-3β inactivation by overexpression of constitutively active GSK-3β (S9A) completely suppressed the CSE-induced up-regulation of IL-17R expression and the CSEinduced enhancement of IL-8 secretion. In conclusion, inactivation of GSK-3β via the PI3K/Akt pathway mediates CSEinduced up-regulation of IL-17R, which contributes to the enhancement of IL-17A-induced IL-8 production. 
Keywords: Akt, cigarette smoke extract, GSK-3β, IL-17A, IL17R, IL-8   

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