The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced induced IL-8 production in human bronchial epithelial cells

Kwok Wai LAU, Stanley Chi Hang CHAN, Andrew Chi Kin LAW, Mary Sau Man IP, Judith Choi Wo MAK

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32 Citations (Scopus)

Abstract

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. Copyright © 2011 The Author.

Original languageEnglish
Pages (from-to)569-577
JournalToxicological Sciences
Volume125
Issue number2
Early online date01 Nov 2011
DOIs
Publication statusPublished - Feb 2012

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Ketanserin
Interleukin-8
Smoke
Tobacco Products
Epithelial Cells
Glutathione Disulfide
Pulmonary diseases
Chronic Obstructive Pulmonary Disease
Anti-Inflammatory Agents
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Small Interfering RNA
Receptor, Serotonin, 5-HT2A
Phosphorylation
Glutathione
Western Blotting
Smoking
Inflammation
Cell Line

Citation

Lau, W. K. W., Chan, S. C. H., Law, A. C. K., Ip, M. S. M., & Mak, J. C. W. (2012). The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced induced IL-8 production in human bronchial epithelial cells. Toxicological Sciences, 125(2), 569-577. doi: 10.1093/toxsci/kfr305

Keywords

  • Chronic obstructive pulmonary disease
  • Cigarette smoke
  • Human bronchial epithelial cells
  • Interleukin-8
  • Serotonin