PPARα transcriptionally induces AhR expression in Caco-2, but represses AhR pro-inflammatory effects

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Abstract

In this work we demonstrate that Caco-2 cell treatment with WY-14643 (a potent PPARα agonist) causes an increase in AhR expression. Luciferase assays and directed mutagenesis experiments showed that induction mainly occurred at transcriptional level and involved a PPRE site located within the AhR promoter. These results were further confirmed by the use of PPARα knockout mice in which AhR induction by WY14643 was abrogated. In addition to CYP1 regulation, AhR has been described as being involved in inflammation, so we also studied the effect of AhR regulation by PPARα on the expression of some inflammation target genes. 3-Methylcholanthrene (a potent AhR agonist) increased the expression (mRNA) of the major inflammatory targets IL-1β and MMP9. WY-14643 co-treatment abrogated the 3-methylcholanthrene pro-inflammatory effect. Hence the anti-inflammatory effect of PPARα overrides the pro-inflammatory effect of AhR.

Section snippets

Materials and methods

Chemicals. WY was from VWR International (Fontenay-sous-Bois, France); 3MC, dimethylsulfoxide (DMSO), and bovine serum albumin (BSA) were from Sigma (Saint-Quentin-Fallavier, France).

Cell culture. Caco-2 cells from human colorectal adenocarcinoma [8] were a generous gift from Dr. Le Bivic (IBDM, Marseille, France). Cells were maintained in Dulbecco’s modified Eagle’s medium (Eurobio, Les Ulis, France) supplemented with 10% fetal bovine serum (FBS) (Eurobio), 2 mM l-glutamine (Life Technologies,

Effects of WY exposure on AhR expression in Caco-2 cells

As shown in Fig. 1A, treatment of Caco-2 cells with increasing amounts of WY led to an induction of AhR expression, with a maximum effect with 100 μM WY (3.5-fold, p < 0.01). The transcript induction was associated with an increase in protein expression (Fig. 2) in the cytoplasm and nucleus.

Effects of WY treatment on colic expression of AhR in wild type and PPARα knockout mice

To verify in vivo that WY exposure leads to an induction of AhR expression, wild type mice and PPARα knockout mice were treated with 30 mg/kg of WY. As shown in Fig. 1B, WY enhanced AhR mRNA expression in the

Discussion

Substances in the environment, including the diet, exert their biological effects by modulating the activity of transcription factors. We previously reported that PPARα activation potentiated CYP1A1 induction mediated by the AhR pathway [7], but the molecular events involved in this effect were not known.

Here we find that this potentiation is probably partly due to a transcriptional activation of AhR expression by PPARα ligand (WY). This agrees with the results we obtained with PPARα KO mice,

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