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: Ivan Monteleone, Francesca Zorzi, Irene Marafini, Davide Di Fusco, Vincenzo Dinallo, Roberta Caruso, Roberta Izzo, Eleonora Franzè, Alfredo Colantoni, Francesco Pallone, Giovanni Monteleone
• Journal: European journal of immunology (Eur J Immunol) Vol. 46 Issue 4 Pg. 1047-57 (Apr 2016) ISSN: 1521-4141 [Electronic] Germany
• PMID: 26786786 (Publication Type: Journal Article)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
• ACTA2 protein, human
• Actins
• Azo Compounds
• COL3A1 protein, human
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Collagen Type III
• Pyrazoles
• Receptors, Aryl Hydrocarbon
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Trinitrobenzenesulfonic Acid
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Actins (biosynthesis)
• Adult
• Aged
• Animals
• Azo Compounds (pharmacology)
• Collagen Type I (biosynthesis)
• Collagen Type I, alpha 1 Chain
• Collagen Type III (biosynthesis)
• Constriction, Pathologic (pathology)
• Crohn Disease (pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblasts (metabolism)
• Fibrosis (chemically induced, pathology)
• Gastrointestinal Tract (metabolism, pathology)
• Humans
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Pyrazoles (pharmacology)
• Receptors, Aryl Hydrocarbon (agonists, antagonists & inhibitors, genetics, metabolism)
• Transforming Growth Factor beta1 (pharmacology)
• Trinitrobenzenesulfonic Acid (toxicity)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)