β-Catenin signaling is required for TGF-β₁-induced extracellular matrix production by airway smooth muscle cells

Abstract

Chronic inflammatory airway diseases like asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway remodeling with altered extracellular matrix (ECM) deposition. Transforming growth factor-β1 (TGF-β1) is upregulated in asthma and COPD and contributes to tissue remodeling in the airways by driving ECM production by structural cells, including airway smooth muscle. In this study, we investigated the activation of β-catenin signaling and its contribution to ECM production by airway smooth muscle cells in response to TGF-β1. Stimulation of airway smooth muscle cells with TGF-β1 resulted in a time-dependent increase of total and nonphosphorylated β-catenin protein expression via induction of β-catenin mRNA and inhibition of GSK-3. In addition, the TGF-β1-induced β-catenin activated TCF/LEF-dependent gene transcription, as determined by the β-catenin sensitive TOP-flash luciferase reporter assay. Furthermore, TGF-β1 stimulation increased mRNA expression of collagen Iα1, fibronectin, versican, and PAI-1. Pharmacological inhibition of β-catenin by PKF115-584 or downregulation of β-catenin expression by specific small interfering RNA (siRNA) substantially inhibited TGF-β1-induced expression of the ECM genes. Fibronectin protein deposition by airway smooth muscle cells in response to TGF-β1 was also inhibited by PKF115-584 and β-catenin siRNA. Moreover, transfection of airway smooth muscle cells with a nondegradable β-catenin mutant (S33Y β-catenin) was sufficient for inducing fibronectin protein expression. Collectively, these findings indicate that β-catenin signaling is activated in response to TGF-β1 in airway smooth muscle cells, which is required and sufficient for the regulation of ECM protein production. Targeting β-catenin-dependent gene transcription may therefore hold promise as a therapeutic intervention in airway remodeling in both asthma and COPD.

TGF‐β‐induced profibrotic signaling is regulated in part by the WNT receptor Frizzled‐8

“…We furthermore showed that TGFb-induced fibronectin and a-sm-actin expression was dependent on b-catenin (10,11). This underscores the role of WNT signaling in fibroblast activation and remodeling as well as the cross-talk that exists between TGF-b and WNT signaling in these responses.…”

“…Recent findings indicate similar key roles for the Wingless/integrase-1 (WNT) signaling pathway in tissue homeostasis and remodeling in many organ systems, including the lung (8)(9)(10)(11)(12). WNT ligands bind to transmembrane Frizzled (FZD) receptors and can thereby control cell differentiation, growth, and polarity in a variety of cell systems.…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…4) (9,79,121,163,201,216,217,347). For example, expression of contractile proteins is enhanced in human ASM cells exposed to both methacholine and TGF-␤ (216,217).…”

Low levels of TGF-β1 enhance human umbilical cord-derived mesenchymal stem cell fibronectin production and extend survival time in a rat model of lipopolysaccharide-induced acute lung injury

“…Transforming growth factor (TGF)-β1 stimulates ECM synthesis in cultured cells, including renal, vascular smooth muscle and type-II pulmonary epithelial cells (20)(21)(22). TGF-β1 is also involved in MSC proliferation (23).…”