The aryl hydrocarbon receptor (AhR) is an important nuclear transcription factor that is best known for mediating toxic responses by adjusting numbers of metabolism-related enzymes, including CYP1A1 and CYP1B1. Previous findings have revealed that, in addition to negatively regulating cell proliferation and survival, AhR may also positively regulate these pathways. Here, we review these findings and summarize distinct mechanisms by which AhR promotes cell proliferation and survival, including modulation of receptor expression, growth factor signalling and apoptosis, regulating the cell cycle and promoting cytokine expression. This review will aid better understanding the role of AhR in positive regulation of cell proliferation and survival.

The pathogenesis of inflammatory bowel disease (IBD) is believed to be associated with the abnormal expression of inflammatory factors. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, which can suppress the inflammatory response and attenuate experimental colitis. However, the detailed mechanism underlying the effects of AhR remains unclear. The present study investigated the role of AhR in the pathogenesis of IBD. Colitis was induced in mice by administration of 3% dextran sulphate sodium (DSS) for 7 days. The mice were also administered injections of the AhR agonist, 6-formylindolo(3,2-b)carbazole (FICZ), starting 2 days after the first administration of DSS. Furthermore, LoVo cells were treated with lipopolysaccharide (LPS) in the presence or absence of FICZ for 8 h. The protein expression levels of AhR, cytochrome P450 1A1 (CYP1A1) and tristetraprolin (TTP) were assessed by western blotting and immunofluorescence, whereas mRNA expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. The results indicated that injection of mice with FICZ significantly attenuated DSS-induced colitis; in addition, the expression levels of inflammatory cytokines were markedly downregulated. Conversely, the expression levels of AhR and TTP were upregulated. In addition, mice in the AhR-knockout + DSS group exhibited elevated inflammatory cytokine production and developed more severe colitis. In LoVo cells, incubation with FICZ decreased the expression levels of inflammatory cytokines, whereas AhR and TTP expression was increased. In addition, the levels of phosphorylated-mitogen-activated protein kinase-activated protein kinase 2 (p-MK2) were decreased. These results suggested that AhR deficiency resulted in increased susceptibility to colitis, whereas activation of AhR by FICZ could ameliorate DSS-induced colitis via the MK2/p-MK2/TTP pathway.

Intestinal ischemia/reperfusion (I/R) induces disruption of the intestinal barrier function. Aryl hydrocarbon receptor (AhR) has a vital role in maintaining the intestinal barrier function. However, the precise mechanism by which AhR maintains intestinal barrier function remains unclear. Notch1 signaling is downstream of AhR, and has also been reported to have a role in the development of tight junctions (TJs) and maintenance of intestinal homeostasis. Therefore, we hypothesized that AhR activation may attenuate the intestinal barrier dysfunction through increased activation of Notch1 signaling. Adult C57BL/6J mice were divided into three groups: Sham, I/R and I/R + 6-formylindolo(3,2-b) carbazole (Ficz) groups. Mice were sacrificed after I/R for 6 h and the intestine was harvested for histological examination, mRNA and protein content analysis, and mucosal permeability investigation. Additionally, a hypoxic Caco-2 cell culture model was used to evaluate the role of AhR-Notch1 signaling in the development of TJs and epithelial permeability in vitro. The AhR-Notch1 signaling components and TJ proteins were assessed by reverse transcription-quantitative polymerase chain reaction, western blotting, immunohistochemistry or immunofluorescence staining. Epithelial permeability was detected by transepithelium electrical resistance. The data demonstrated that Ficz significantly attenuated the intestinal tissue damage and the disrupted distribution of TJs, increased the expression of TJ proteins, reversed the decrease in TER and upregulated epithelial Notch1 signaling following intestinal I/R in vivo and hypoxia in vitro. Furthermore, inhibition of Notch1 signaling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (inhibitor of Notch signaling) counteracted the effects of Ficz on the development of TJs in hypoxic Caco-2 cells. In conclusion, AhR activation ameliorated epithelial barrier dysfunction following intestinal I/R and hypoxia through upregulation of Notch1 signaling, which suggests that AhR may be a potential pharmaceutical agent to combat this condition.