Porcine interleukin-6 enhances the expression of CYP2C33 through a constitutive androstane receptor/retinoid X receptor-mediated pathway

<p></p><p>Cytochrome P450, which is expressed in humans and other animals, is a superfamily of drug-metabolizing enzymes that play important roles in the metabolism of endogenous and xenobiotic substrates via oxidation, peroxidation and reduction. Of endogenous substrates, interleukin (IL)-6 is a crucial cytokine involved in inflammation in the liver. The present study aims to elucidate the mechanisms through which IL-6 modulates cytochrome P450 expression.</p><p>CYP2C33 expression was found to be increased in HepLi cells and primary porcine hepatocytes treated with IL-6 in a concentration-dependent manner. IL-6 treatment also increased the expression of the transcriptional regulators, constitutive androstane receptor (CAR) and pregnane X receptor.</p><p>Overexpression of CAR promoted CYP2C33 expression at the mRNA and protein levels, whereas knockdown of CAR by small interfering RNA reduced CYP2C33 expression. Luciferase assays showed that IL-6 treatment of HepLi cells and primary porcine hepatocytes increased <i>CYP2C33</i> promoter activity. Co-immunoprecipitation and western blotting demonstrated that CAR and RXR could form heterodimers.</p><p>IL-6 affects CYP2C33 expression through CAR/retinoid X receptor (RXR) heterodimers.</p><p></p> <p>Cytochrome P450, which is expressed in humans and other animals, is a superfamily of drug-metabolizing enzymes that play important roles in the metabolism of endogenous and xenobiotic substrates via oxidation, peroxidation and reduction. Of endogenous substrates, interleukin (IL)-6 is a crucial cytokine involved in inflammation in the liver. The present study aims to elucidate the mechanisms through which IL-6 modulates cytochrome P450 expression.</p> <p>CYP2C33 expression was found to be increased in HepLi cells and primary porcine hepatocytes treated with IL-6 in a concentration-dependent manner. IL-6 treatment also increased the expression of the transcriptional regulators, constitutive androstane receptor (CAR) and pregnane X receptor.</p> <p>Overexpression of CAR promoted CYP2C33 expression at the mRNA and protein levels, whereas knockdown of CAR by small interfering RNA reduced CYP2C33 expression. Luciferase assays showed that IL-6 treatment of HepLi cells and primary porcine hepatocytes increased <i>CYP2C33</i> promoter activity. Co-immunoprecipitation and western blotting demonstrated that CAR and RXR could form heterodimers.</p> <p>IL-6 affects CYP2C33 expression through CAR/retinoid X receptor (RXR) heterodimers.</p>