Blockage of serotonin receptor 2 attenuates cigarette-induced IL-8 release in human bronchial epithelial cells

Abstract

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway limitation together with abnormal inflammation in the lung. Cigarette smoke (CS) is one of the major causes of this disease, involving the induction of inflammatory responses in the airway with increase in pro-inflammatory cytokines, i.e. interleukin-8 (IL-8). Increased systemic serotonin (5-HT) level in non-smokers after inhaling cigarette smoke (Clin Investig 1992;70:201-204) and improved lung function in COPD patients after selective serotonin receptor 2 antagonist, ketanserin (Chest 1990;97:901-905), suggest the involvement of serotoninergic system in COPD. Recently, 5-HTR2 has been found to be expressed in human lung epithelial cells and exposure to 5-HT or R-(-)-DOI-hydrochloride (DOI), a selective 5-HTR2 agonist, elevated IL-8 release (Am J Respir Cell Mol Biol 2007;36:85-93). We therefore hypothesize that serotonin is involved in CS-induced IL-8 release via activation of 5-HTR2 in human bronchial epithelial cells. The present study aims at investigating the mechanisms on how CS modulates 5-HT, leading to elevated IL-8 release in BEAS-2B cells. METHODS: Expression of 5-HTR2 subtypes and IL-8 mRNA was examined by RT-PCR. IL-8 release was determined by ELISA. Activation of MAPK pathway was assessed by Western-blot. RESULTS: We confirmed the mRNA expression of 5-HTR2 subtype in BEAS-2B cells. After exposure to CS or 5-HT, the mRNA expression as well as the release of IL-8 was elevated in parallel with the increased expression of phosphorylated ERK1/2 and p38 but not JNK. Ketanserin was found to suppress CS-induced IL-8 release by inhibiting ERK1/2 and p38 activation. CONCLUSION: These data suggest that 5-HTR2 may be involved in CS-induced IL-8 release via activation of ERK1/2 and p38 pathways in BEAS-2B cells.