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.

AhR activation can ameliorate epithelial barrier dysfunction induced by IO through the suppression of MLCK-pMLC signaling, suggesting that AhR agonist may be a suitable means of addressing this condition.

Inflammatory bowel disease is a kind of multi-aetiological chronic disease that is driven by multidimensional factors. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in anti-inflammatory and cellular responses to hypoxia. Previous studies have found that B or T-cell-specific HIF-1α knock out mice exhibit severe colonic inflammation. However, we know very little about other functions of HIF-1α in intestinal epithelial cells (IECs). In our study, HIF-1α ΔIEC mice were used to study the function of HIF-1α in IECs. HIF-1α was knocked down in Caco-2 cells by transfection with a small interfering (si) RNA. Immunohistochemical staining and western blotting were used to detect the expression of zonula occluden-1 (ZO-1) and Occludin. The content of colon was harvested for high-performance liquid chromatography analysis to examine the levels of butyrate in the gut. Our research found that HIF-1α played a protective role in dextran sulphate sodium-induced colitis, which was partly due to its regulation of tight junction (TJ) protein expression. Further study revealed that HIF-1α mediated TJ proteins levels by moderating the content of butyrate. Moreover, we found that butyrate regulated TJ protein expression, which is dependent on HIF-1α. These results indicated that there is a mutual regulatory mechanism between butyrate and HIF-1α, which has an important role in the maintenance of barrier function of the gastrointestinal tract.Abbreviations: CD, Crohn's disease; HIF-1α, hypoxia-inducible factor-1α; HPLC, high-performance liquid chromatography; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; IHC, immunohistochemical; UC, ulcerative colitis; ZO-1, zonula occluden-1 Jiuheng Yin and Chao Zhou are co-first authors.

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The evolution of chronic inflammatory diseases is thought to be due to a combination of host genetic variations and environmental factors that include the alteration of intestinal flora, termed “dysbiosis.” The intestinal mucosal barrier includes a chemical barrier and physical barrier that have important roles in protecting the intestine against inflammatory injury. The chemical barrier includes antimicrobial peptides ( AMP s), and the physical barrier includes a mucous layer, a monolayer of intestinal epithelial cells and cell junctions. The intestinal mucosal barrier is not a static barrier, but rather, it strongly interacts with the gut microbiome and cells of the immune system. Correct expression of AMP s, together with mucus and balanced epithelial cell proliferation, prevents the occurrence of disease. NLRP 6, a member of the nucleotide‐binding domain, leucine‐rich repeat‐containing ( NLR ) innate immune receptor family, participates in the progression of intestinal inflammation and enteric pathogen infections. It has become apparent in recent years that NLRP 6 is important in disease pathogenesis, as it responds to internal ligands that lead to the release of AMP s and mucus, thus regulating the regeneration of intestinal epithelial cells. This review summarizes the activation of NLRP 6 and its protective role in the intestinal epithelial cell.

Some ingredients in foods can activate the aryl hydrocarbon receptor (AhR) and arrest cell proliferation. In this study, we hypothesized that 6-formylindolo [3, 2-b] carbazole (FICZ) arrests the cell cycle in LoVo cells (a colon cancer line) through the AhR. The AhR agonist FICZ and the AhR antagonist CH223191 were used to treat LoVo cells. Real-time PCR and Western blot analyses were performed to detect the expression of the AhR, CYP1A1, CDK4, cyclinD1, cyclin E, CDK2, P27, and pRb. The distribution and activation of the AhR were detected with immunofluorescence. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometric analysis were performed to measure cell viability, cell cycle stage, and apoptosis. Our results show that FICZ inhibited LoVo cell proliferation by inducing G1 cell cycle arrest but had no effect on epithelial apoptosis. Further analysis found that FICZ downregulated cyclinD1 and upregulated p27 expression to arrest Rb phosphorylation. The downregulation of cyclinD1 and upregulation of p27 were abolished by co-treatment with CH223191. We conclude that the AhR, when activated by FICZ (an endogenous AhR ligand), can arrest the cell cycle and block LoVo cell proliferation.

Our study suggests that KGF, AhR, and CYP1A1 are overexpressed in colorectal cancer tissues. Moreover, we reveal a new mechanism by which KGF promotes cell proliferation through the AhR-cyclin D1 pathway in colon cancer cells.