title: The aryl hydrocarbon receptor ligand ITE inhibits TGFβ1-induced human myofibroblast differentiation.
abstract: Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-β1 (TGFβ1). In this study, we demonstrate that TGFβ1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFβ1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFβ1-driven myofibroblast differentiation in AhR(-/-) fibroblasts: Its ability to inhibit TGFβ1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Geniece M
authors.initials: GM
authors.lastname: Lehmann
authors.forename: Xia
authors.initials: X
authors.lastname: Xi
authors.forename: Ajit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Keith C
authors.initials: KC
authors.lastname: Olsen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
authors.forename: Shikha
authors.initials: S
authors.lastname: Gupta
authors.forename: Ann E
authors.initials: AE
authors.lastname: Casey
authors.forename: Krystel R
authors.initials: KR
authors.lastname: Huxlin
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Steven E
authors.initials: SE
authors.lastname: Feldon
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002454:Cell Differentiation; D065633:Cytochrome P-450 CYP1B1; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D058628:Myofibroblasts / Q000166:cytology; D009915:Orbit / Q000166:cytology; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing
chemical_list: C548651:2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester; D005353:Fibronectins; D007211:Indoles; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1