Abstract
Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.
Highlights
The aryl hydrocarbon receptor (AhR) is an evolutionarily conserved nuclear receptor that is widely expressed in multiple organs including brain, liver, lung, and the gastrointestinal (GI) tract[1,2]
Our current findings demonstrate for the first time that 5-HT can induce cytochrome P450 1A1 (CYP1A1) expression via Aryl hydrocarbon receptor (AhR) in intestinal epithelial cells, and that this activation is dependent upon its uptake into the cell via serotonin transporter (SERT)
The classic physiological functions of 5-HT in the GI tract mainly relate to initiation of peristalsis, visceral sensation, and controlling movement of fluid and electrolytes, which are mediated by activation of specific 5-HT receptors (5-HTRs) subtypes
Summary
The aryl hydrocarbon receptor (AhR) is an evolutionarily conserved nuclear receptor that is widely expressed in multiple organs including brain, liver, lung, and the gastrointestinal (GI) tract[1,2]. AhR translocates to the nucleus and dimerizes with co-factors including aryl hydrocarbon receptor nuclear translocator (ARNT), and binds to xenobiotic-responsive units (XREs) to increase expression of AhR-responsive genes. The canonical gene targets of AhR are the cytochrome P450, family 1 enzymes including CYP1A1, which are involved in the metabolism of polycyclic aromatic hydrocarbons and other xenobiotics[3,4]. New gene targets of AhR have been established that are involved in diverse physiological processes including development, hematopoiesis, and immune modulation[1,2,5]. Mice with epithelial AhR deficiency, but not those with macrophage-specific or T-cell specific AhR deficiency, were more sensitive to DSS-induced colitis with increased apoptosis in intestinal epithelia[8]. How SERT deficiency exacerbates severity of intestinal inflammation is not known
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