Cigarette smoke-induced attenuation of the prostaglandin transporter SLCO2A1 expression through aryl hydrocarbon receptor.

Abstract

SLCO2A1 is a prostaglandin transporter and contributes to regulating local concentration of an inflammatory mediator, PGE₂. Since we previously found that cigarette smoke extracts (CSE) reduced Slco2a1 mRNA expression in rat alveolar epithelial cells, the current study aimed to investigate the effect of CSE on human SLCO2A1 mRNA expression across cell lines from organs that are susceptible to tobacco smoking-induced inflammation. 5'-Flanking regions of SLCO2A1 up to 3673 bp upstream of the transcription start site (+1) was sub-cloned into a luciferase (LUC) expression vector, and promoter activity was evaluated by a reporter assay. CSE significantly reduced SLCO2A1 mRNA expression and LUC activity driven by the construct of -3673/+4 in colon epithelial LoVo and Caco-2 and lung mucoepidermoid NCI-H292 cells, but not in liver epithelial-like HepG2 cells. Long-term exposure of LoVo cells to CSE completely suppressed SLCO2A1 protein expression. The CSE-mediated effect on LUC activity was restored by an AHR antagonist PD98059 and a known AHR ligand β-naphthoflavone significantly reduced SLCO2A1 mRNA expression in cells. Concomitantly, the CSE-mediated negative regulation of SLCO2A1 was abolished in cells transfected with the construct of -3673/+4 with mutated xenobiotic response element. Furthermore, PD98059 and an AHR inhibitor perillaldehyde diminished the negative effect of CSE on SLCO2A1 mRNA expression in Lovo, NCI-H292 and Caco-2 cells. These results demonstrate that CSE negatively modulates SLCO2A1 transcription through AHR activation, providing a toxicological implication of tobacco smoke-induced inflammation.