Upregulation of Multidrug Resistance-Associated Protein 1 by Allyl Isothiocyanate in Human Bronchial Epithelial Cell: Involvement of c-Jun N-Terminal Kinase Signaling Pathway.

Shujun Wang,Jie Li,Yajun Chen,Zegeng Li,Ling Fan,Dianlei Wang,Xueqi Wang,Chenyin Wang,Shanshan Wang,Zhaoliang Peng

doi:10.1155/2015/903782

Abstract

Multidrug resistance-associated protein 1 (MRP1) plays a protective role in the etiology and progression of chronic obstructive pulmonary disease (COPD) which results from oxidative stress and inflammation of lung injury. The lower functional MRP1 activity is related to COPD development. Our previous study showed that Allyl isothiocyanate (AITC) induced the expression and activity of MRP1 in a dose-dependent manner. However, which signaling pathway contributes to the upregulation of MRP1 by AITC is unclear. In this study, signaling pathway specific inhibitors were used to examine the mechanism of AITC. We found that JNK inhibitor SP600125 treatment decreased MRP1 mRNA expression in 16HBE14o- cells. But the ERK inhibitor U0126 or PI3K/Akt inhibitor LY294002 produced no obvious effect. The AITC-induced increase of MRP1 mRNA expression was abolished by cotreatment of SP600125, while it was not obviously affected by U0126 or LY294002. Furthermore, AITC acivates the JNK signaling pathway in 16HBE14o- cells. Finally, we found that JNK pathway mediated the upregulation of AITC-induced expression and function of MRP1. Taken together, our results indicated that AITC increased the expression and the activity of MRP1 via a JNK-dependent pathway. ERK and PI3K signaling pathway were not involved in the expression of MRP1 mRNA.

Highlights

Both smoking and ambient airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) are capable of inducing noxious particles or gases in the lung [1], which are the principal risk factors for chronic obstructive pulmonary disease (COPD)
To reveal the mechanism of multidrug resistanceassociated protein 1 (MRP1) mRNA expression induced by Allyl isothiocyanate (AITC), 16HBE14o- cells were pretreated with Jun NH2-terminal kinase (JNK), extracellular signalregulated kinase (ERK), and PI3K/Akt inhibitors for 30 min or 60 min prior to the exposure to AITC for 24 h
U0126 (20 μM) and inhibitor LY294002 (10 μM) produced little effect on AITC-induced MRP1 mRNA expression (Figures 1(a) and 1(b)). These results indicated that JNK but not ERK or PI3K/Akt pathway contributes to AITC-induced MRP1 mRNA expression

Summary

Introduction

Both smoking and ambient airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) are capable of inducing noxious particles or gases in the lung [1], which are the principal risk factors for chronic obstructive pulmonary disease (COPD). Proteins of the ATP-binding cassette (ABC) superfamily, such as the multidrug resistanceassociated protein 1 (MRP1), play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites [2, 3]. The protein level of MRP1 is high in bronchial epithelium. The results showed that the protein expression of the bronchial epithelial MRP1 was significantly decreased in papain and smoking induced COPD rat model [5]. MRP1 is known as an essential factor for maintaining tissue homeostasis to defend certain tissues against the stress from xenobiotic insults, proinflammatory cysteinyl, and a vast array of other endoand xenobiotic organic anions [6]

Methods

Results

Conclusion