Journal Article

The Role of MAPK and Nrf2 Pathways in Ketanserin-Elicited Attenuation of Cigarette Smoke–Induced IL-8 Production in Human Bronchial Epithelial Cells

Way Kwok Wai Lau, Stanley Chi Hang Chan, Andrew Chi Kin Law, Mary Sau Man Ip and Judith Choi Wo Mak

in Toxicological Sciences

Volume 125, issue 2, pages 569-577
Published in print February 2012 | ISSN: 1096-6080
Published online November 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr305
The Role of MAPK and Nrf2 Pathways in Ketanserin-Elicited Attenuation of Cigarette Smoke–Induced IL-8 Production in Human Bronchial Epithelial Cells

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Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR2A) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke–induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke–related COPD.

Keywords: chronic obstructive pulmonary disease; cigarette smoke; human bronchial epithelial cells; interleukin-8; serotonin

Journal Article.  4604 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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