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-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-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 TGF␤1 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 TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 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.

Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase

“…Soluble collagen was measured in cell supernatants as previously described (20). Briefly, 5 l of cell supernatants were applied to a PVDF membrane using a vacuum manifold (Schleicher and Schuell, Keene, NH) under nondenaturing conditions.…”

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

“…ITE has also been shown to possess AHR-independent biologic activity, such as the inhibition of transforming growth factor-b1-mediated myofibroblast differentiation, which prevents fibrosis within human tissue (Lehmann et al, 2011). The AHR ligand ITE has many biologic activities, but its classification as an "endogenously" derived compound remains to be established.…”

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

“…This finding is consistent with our report that the AHR ligand ITE blocked myofibroblast formation in mouse lung fibroblasts. 37 Another recent report reveals that the AHR ligand kynurenine prevents collagen production in dermal fibroblasts and possesses antifibrotic properties in a mouse model of skin scarring. 40 Myofibroblasts also express high levels of a-SMA, which localize to large stress fibers.…”

“…This result is in some contrast to our earlier study in which it was observed that ITE's ability to block myofibroblast formation was largely AHR independent. 37 However, this study was performed in fibroblasts derived from either wild-type or AHR knockout mouse lung tissue. The different findings could be a result of either species-or tissue-specific differences in the AHR and TGF-b pathways.…”