title: Aryl hydrocarbon receptor-driven signals inhibit collagen synthesis in the gut.
abstract: Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF-β1 or TNF-α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR-silencing RNA. In CD fibroblasts, TGF-β1 and TNF-α increased Col1A1, Col3A1 and α-SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF-β1 or TNF-α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene-sulfonic-acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut.
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zorzi
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Di Fusco
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dinallo
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Izzo
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzè
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colantoni
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.affiliation: Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000096:biosynthesis; D003251:Constriction, Pathologic / Q000473:pathology*; D003424:Crohn Disease / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; C541116:ACTA2 protein, human; D000199:Actins; D001391:Azo Compounds; C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Aryl hydrocarbon receptor; Collagen; Crohn's disease; Fibroblasts; Strictures