The cigarette smoke induced attenuation of SLCO2A1 expression is through Aryl hydrocarbon receptor (AhR) activation

抄録

SLCO2A1 is a prostaglandin transporter in the body. Our laboratory’s previous research implied its role in inflammation regulation via PGE2 transport. We also found that cigarette smoke extracts (CSE) reduced SLCO2A1 function and expression in alveolar epithelial cells derived from mouse lungs. This study aimed to explore the effect of CSE on human SLCO2A1 mRNA expression and promoter activity across cell lines from organs susceptible to smoking-induced inflammation (lung, gut, and liver). We investigated the effect of CSE alongside AhR inhibition using perrialdehyde (PAH) and PD98059 on SLCO2A1 mRNA expression in different cell lines (such as LoVo, HepG2, NCI-H292). Most cell lines exhibited reduced SLCO2A1 mRNA expression after CSE treatment, except HepG2. Treatment with PAH and PD98059 restored SLCO2A1 mRNA levels after CSE exposure, indicating that AhR signaling is involved in CSE-mediated SLCO2A1 downregulation. Luciferase reporter assays using various SLCO2A1 promoter constructs (from 0.2 to 3.7kb upstream of transcription starting site) revealed significantly decreased activity with CSE in pGL3/3.7k promoter construct, and only PD98059 restored activity after CSE treatment, implying that CSE reduces SLCO2A1 transcription via AhR. Mutations in two AhR consensus sites within the promoter region restored luciferase activity after CSE treatment, affirming that there is an AhR and DNA interaction for SLCO2A1 transcription. In summary, CSE negatively modulates SLCO2A1 expression through AhR/DNA interaction.