PPARalpha transcriptionally induces AhR expression in Caco-2, but represses AhR pro-inflammatory effects.
In this work we demonstrate that Caco-2 cell treatment with WY-14643 (a potent PPARalpha 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 PPARalpha 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 PPARalpha on the expression of some inflammation target genes. 3-Methylcholanthrene (a potent AhR agonist) increased the expression (mRNA) of the major inflammatory targets IL-1beta and MMP9. WY-14643 co-treatment abrogated the 3-methylcholanthrene pro-inflammatory effect. Hence the anti-inflammatory effect of PPARalpha overrides the pro-inflammatory effect of AhR.
Villard
P H
PH
INSERM, U476 "Nutrition Humaine et Lipides", Marseille F-13385, France. pierre-henri.villard@univmed.fr
Caverni
S
S
Baanannou
A
A
Khalil
A
A
Martin
P G
PG
Penel
C
C
Pineau
T
T
Seree
E
E
Barra
Y
Y
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D018938:Caco-2 Cells; D002460:Cell Line; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015533:Transcriptional Activation
D051792:Basic Helix-Loop-Helix Proteins; D018836:Inflammation Mediators; D047493:PPAR alpha; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse