Activation of the NFκB Pathway Enhances AhR Expression in Intestinal Caco-2 Cells

S Champion,Y Barra,P Bremond,P H Villard,E Seree,J Abraldes,K Benbrahim,C Sauzet

doi:10.1155/2013/792452

Abstract

Recent data suggest that apart from its well-known role in the regulation of xenobiotic metabolizing enzymes, AhR is also involved in inflammation. However, the influence of inflammation on AhR expression remains unknown. Here, we demonstrated that proinflammatory conditions induced by either PMA or IL-1β enhance AhR expression in Caco-2 cells. This was associated with an increase in AhR promoter activity. By means of directed mutagenesis experiments and the use of proteasome inhibitors, we demonstrated that inflammation-induced AhR expression involved the NFκB pathway but not AP-1. Moreover, conditioned media from PMA-treated Caco-2 cells were also able to induce AhR expression, and this induction was repressed by anti-IL-1β blocking antibodies. Similar results were obtained with conditioned media from PMA-treated THP-1 cells. Taken together, these data suggest that AhR could be involved in vivo in an inflammatory loop. AhR was recently suspected to be implicated in inflammatory bowel disease. Our results support this hypothesis and suggest that AhR could be a new target for inflammatory bowel disease patient management.

Highlights

The aryl hydrocarbon receptor (AhR) is a transcription factor activated by numerous environmental ligands such as dioxins and polycyclic aromatic hydrocarbons (PAHs) [1]
AhR is known to be a key regulator of some xenobiotic degradation enzymes, notably cytochromes P450 belonging to the CYP1 family, which are involved in the bioactivation of various environmental procarcinogens including PAH and arylamines
In order to evaluate the effect of proinflammatory conditions on AhR mRNA levels, Caco-2 cells were treated with phorbol 12-myristate 13-acetate (PMA) or with IL-1β

Summary

Introduction

The aryl hydrocarbon receptor (AhR) is a transcription factor activated by numerous environmental ligands such as dioxins and polycyclic aromatic hydrocarbons (PAHs) [1]. AhR translocates to the nucleus, dimerizes with its partner the aryl hydrocarbon receptor nuclear translocator (ARNT), and binds to xenobiotic responsive elements (XRE) in target genes. AhR is known to be a key regulator of some xenobiotic degradation enzymes, notably cytochromes P450 belonging to the CYP1 family, which are involved in the bioactivation of various environmental procarcinogens including PAH and arylamines. Accidental exposure to dioxins, which are prototypes of environmental AhR ligands, leads to a broad spectrum of pathologies, ranging from cancers to cardiovascular diseases and type 2 diabetes [4,5,6], all of which involve an inflammatory process. We have shown in intestine that PAH-induced AhR activation upregulates the expression of some inflammation

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Conclusion