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Activation of the NF κ B Pathway Enhances AhR Expression in Intestinal Caco-2 Cells.

Champion S, Sauzet C, Bremond P, Benbrahim K, Abraldes J, Seree E, Barra Y, Villard PH - ISRN Toxicol (2013)

Bottom Line: This was associated with an increase in AhR promoter activity.Similar results were obtained with conditioned media from PMA-treated THP-1 cells.Our results support this hypothesis and suggest that AhR could be a new target for inflammatory bowel disease patient management.

View Article: PubMed Central - PubMed

Affiliation: IMBE-UMR CNRS 7263, IRD 237 Aix-Marseille Université Campus Timone, Faculté de Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille Cedex 05, France.

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-1 β 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 NF κ B 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-1 β 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.

No MeSH data available.


Related in: MedlinePlus

Hypothetical role of the AhR pathway in the development of inflammatory bowel disease after exposure to environmental PAH. B(a)P: benzo(a)pyrene; BPDE: benzo(a)pyrene diol epoxide.
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fig6: Hypothetical role of the AhR pathway in the development of inflammatory bowel disease after exposure to environmental PAH. B(a)P: benzo(a)pyrene; BPDE: benzo(a)pyrene diol epoxide.

Mentions: The environment exposes us to various AhR ligands that could modulate susceptibility to inflammation. PAHs are potent AhR ligands that are present in tobacco smoke as well as diet, notably grilled meats. Cigarette smoking is emerging as a strong risk factor in the otherwise unknown etiology of chronic inflammatory diseases [17]. There are reports of a dose-response relationship between exposure to tobacco smoke and inflammatory bowel disease (IBD) [18]. The exact mechanisms by which smoking influences the development of IBD are poorly understood, but nicotine does not appear to play a critical role [18]. Interestingly, a recent study in dextran sulfate sodium-induced colitis mice reported that the attenuation of AhR expression resulted in a protective effect [19]. Moreover, AhR and its downstream targets, such as IL-8, were significantly upregulated in IBD patients versus controls. The authors concluded that abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation [19], and our results support this hypothesis. Figure 6 proposes a possible explanation of the link between the AhR pathway and IBD. PAHs such as benzo(a)pyrene, are bioactivated by CYP1 family enzymes into diolepoxides, such as benzo(a)pyrene diol epoxide [20], which activate NFκB [16]. The activation of NFκB promotes an inflammatory loop via IL-1β expression and induces AhR expression. The upregulation of AhR would, in response to PAH exposure, enhance both CYP1 inducibility and PAH-inflammatory properties.


Activation of the NF κ B Pathway Enhances AhR Expression in Intestinal Caco-2 Cells.

Champion S, Sauzet C, Bremond P, Benbrahim K, Abraldes J, Seree E, Barra Y, Villard PH - ISRN Toxicol (2013)

Hypothetical role of the AhR pathway in the development of inflammatory bowel disease after exposure to environmental PAH. B(a)P: benzo(a)pyrene; BPDE: benzo(a)pyrene diol epoxide.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818893&req=5

fig6: Hypothetical role of the AhR pathway in the development of inflammatory bowel disease after exposure to environmental PAH. B(a)P: benzo(a)pyrene; BPDE: benzo(a)pyrene diol epoxide.
Mentions: The environment exposes us to various AhR ligands that could modulate susceptibility to inflammation. PAHs are potent AhR ligands that are present in tobacco smoke as well as diet, notably grilled meats. Cigarette smoking is emerging as a strong risk factor in the otherwise unknown etiology of chronic inflammatory diseases [17]. There are reports of a dose-response relationship between exposure to tobacco smoke and inflammatory bowel disease (IBD) [18]. The exact mechanisms by which smoking influences the development of IBD are poorly understood, but nicotine does not appear to play a critical role [18]. Interestingly, a recent study in dextran sulfate sodium-induced colitis mice reported that the attenuation of AhR expression resulted in a protective effect [19]. Moreover, AhR and its downstream targets, such as IL-8, were significantly upregulated in IBD patients versus controls. The authors concluded that abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation [19], and our results support this hypothesis. Figure 6 proposes a possible explanation of the link between the AhR pathway and IBD. PAHs such as benzo(a)pyrene, are bioactivated by CYP1 family enzymes into diolepoxides, such as benzo(a)pyrene diol epoxide [20], which activate NFκB [16]. The activation of NFκB promotes an inflammatory loop via IL-1β expression and induces AhR expression. The upregulation of AhR would, in response to PAH exposure, enhance both CYP1 inducibility and PAH-inflammatory properties.

Bottom Line: This was associated with an increase in AhR promoter activity.Similar results were obtained with conditioned media from PMA-treated THP-1 cells.Our results support this hypothesis and suggest that AhR could be a new target for inflammatory bowel disease patient management.

View Article: PubMed Central - PubMed

Affiliation: IMBE-UMR CNRS 7263, IRD 237 Aix-Marseille Université Campus Timone, Faculté de Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille Cedex 05, France.

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-1 β 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 NF κ B 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-1 β 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.

No MeSH data available.


Related in: MedlinePlus