Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract

Monteleone, Ivan; Rizzo, Angelamaria; Sarra, Massimiliano; Sica, Giuseppe; Sileri, Pierpaolo; Biancone, Livia; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.1053/j.gastro.2011.04.007

Cited by 493 publications

(493 citation statements)

References 35 publications

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“…FICZ also is bound to the AHR with the highest affinity known to date and thereby demonstrates the characteristics of an endogenous signaling molecule; i.e., it stimulates an efficient receptor-mediated pathway for transcriptional activation of metabolic enzymes that, among other things, catalyze the clearance of FICZ itself, thereby generating negative feedback regulation of its action (3,26,27). The physiological effects of FICZ reported to date include alterations in circadian rhythms (28), adaptive responses to UV light (4,29), induced retrotransposition of long interspersed nucleotide element-1 (30), and stimulated production of IL-22, a member of the IL-10 cytokine family that helps regulate inflammatory responses associated with many autoimmune diseases (17,18,31). In humans, the involvement of FICZ in IL-22 production has been demonstrated both in stimulated blood cells from the umbilical cord (32) and in intestinal tissue from patients with inflammatory bowel disease (31).…”

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confidence: 99%

“…The physiological effects of FICZ reported to date include alterations in circadian rhythms (28), adaptive responses to UV light (4,29), induced retrotransposition of long interspersed nucleotide element-1 (30), and stimulated production of IL-22, a member of the IL-10 cytokine family that helps regulate inflammatory responses associated with many autoimmune diseases (17,18,31). In humans, the involvement of FICZ in IL-22 production has been demonstrated both in stimulated blood cells from the umbilical cord (32) and in intestinal tissue from patients with inflammatory bowel disease (31).…”

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confidence: 99%

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Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Wincent

Bengtsson²,

Bardbori³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

177

215

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Altered systemic levels of 6-formylindolo [3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3′-methoxy-4′-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.

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confidence: 99%

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Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Wincent

Bengtsson²,

Bardbori³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

177

215

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“…The binding to its agonist allows AhR nuclear translocation and regulation of a large number of target genes containing dioxin responsive elements on their enhancer sequences (1). Recent data demonstrate that AhR influences immune responses and is involved in inflammatory diseases, such as experimental autoimmune encephalomyelitis (2), inflammatory bowel disease (3), and inflammatory response to cigarette smoke (4). Several groups have shown that AhR activation contributes to IL-17-producing T cell (Th17) differentiation (5), whereas others have reported that it induces natural CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and IL-10-producing Tr1 cells (6).…”

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confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Sibilano

Frossi

Calvaruso

et al. 2012

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

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“…This finding is consistent with the demonstration that CD mucosal T cells are not responsive to Tregs-mediated immunosuppression, a phenomenon that is reverted by Smad7 knockdown. T cells of Smad7-transgenic mice also exhibit a defective expression of aryl hydrocarbon receptor (AhR), a transcription factor that promotes IL-22 production thus delivering protective signals in the gut [37]. In immunodeficient mice, 6-formylindolo [3,2-b]carbazole, an activator of AhR, ameliorates colitis induced by wild-type T cells but does not affect colitis induced by transfer of Smad7-overexpressing T cells [37].…”

Section: Preclinical Evidence Supporting the Immunoregulatory Effect mentioning

confidence: 99%

Smad7 as a Target for Immunomodulation Strategy in Inflammatory Bowel Diseases

Sedda¹,

Troncone²,

Imeneo³

et al. 2017

Immunome Res

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Inflammatory bowel diseases (IBD) are chronic inflammatory pathologies of the gut, characterized by a relapsingremitting course. Although IBD pathogenesis is not fully understood, epidemiological and experimental data suggest that multiple environmental factors can, in genetically predisposed individuals, trigger an excessive immune response directed against the antigens of the normal intestinal microflora, which eventually leads to the tissue damage. Defects in the physiological mechanisms/factors of counter-regulation contribute to amplify and sustain such a detrimental response. For instance, in inflamed tissue of IBD patients there is diminished activity of the immunesuppressive cytokine transforming growth factor (TGF)-β1, due to elevated levels of Smad7, an intracellular inhibitor of TGF-β1 signaling. Consistently, knockdown of Smad7 with a specific antisense oligonucleotide suppresses inflammatory signals in cultured intestinal cells of IBD patients and in the gut of mice with IBD-like experimental colitis. Moreover, treatment of patients with active Crohn's disease, one of the two major IBD in human beings, with Mongersen, an oral compound containing Smad7 antisense oligonucleotide, is accompanied by induction of clinical remission. Altogether these data indicate that targeting Smad7 represents a promising approach to modulate the ongoing mucosal inflammation in IBD.

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Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract

Abstract: AhR is down-regulated in intestinal tissue of patients with IBD; AhR signaling, via IL-22, inhibits inflammation and colitis in the gastrointestinal tract of mice. AhR-related compounds might be developed to treat patients with IBDs.

Cited by 493 publications

References 35 publications

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Smad7 as a Target for Immunomodulation Strategy in Inflammatory Bowel Diseases

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