Fn14, a Downstream Target of the TGF-β Signaling Pathway, Regulates Fibroblast Activation

Abstract

Fibrosis, the hallmark of human injuries and diseases such as serious burns, is characterized by excessive collagen synthesis and myofibroblast accumulation. Transforming growth factor-β (TGF-β), a potent inducer of collagen synthesis, has been implicated in fibrosis in animals. In addition to TGF-β, fibroblast growth factor-inducible molecule 14 (Fn14) has been reported to play an important role in fibrotic diseases, such as cardiac fibrosis. However, the function and detailed regulatory mechanism of Fn14 in fibrosis are unclear. Here, we investigated the effect of Fn14 on the activation of human dermal fibroblasts. In normal dermal fibroblasts, TGF-β signaling increased collagen production and Fn14 expression. Furthermore, Fn14 siRNA blocked extracellular matrix gene expression; even when TGF-β signaling was activated by TGF-β1, fibroblast activation remained blocked in the presence of Fn14 siRNA. Overexpressing Fn14 increased extracellular matrix gene expression. In determining the molecular regulatory mechanism, we discovered that SMAD4, an important TGF-β signaling co-mediator, bound to the Fn14 promoter and activated Fn14 transcription. Taken together, these results indicate that the TGF-β signaling pathway activates Fn14 expression through the transcription factor SMAD4 and that activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation. Therefore, Fn14 may represent a promising approach to preventing the excessive accumulation of collagen or ECM in skin fibrosis.

TWEAK/Fn14 Signals Mediate Burn Wound Repair

“…Moreover, the mRNA expression levels of both TWEAK and Fn14 are increased in skeletal muscles of burn patients (Merritt et al, 2013). Fn14 expression increases extracellular matrix synthesis and fibroblast activation in patients with thermal burns (Chen et al, 2015). These findings indicated that TWEAK/Fn14 signals may also be associated with skin wounds.…”

“…The downstream cytokines or receptors regulated by TWEAK/ Fn14 signals include RANTES, MCP-1, IP-10, and EGFR, which function vitally in collagen synthesis and tissue remodeling in skin (Kim et al, 2014;Liu Q et al, 2017;Nosbaum et al, 2016;Rayego-Mateos et al, 2013;Wen et al, 2013;Xia et al, 2012). TGF-b also regulates the activation of dermal fibroblasts through Fn14 signals (Chen et al, 2015). In fact, TWEAK/Fn14 signals participate in the progression of various skin diseases, such as cutaneous lupus erythematosus (Doerner et al, 2015;Liu Y et al, 2017b), systemic sclerosis (Sargent et al, 2016), and psoriasis (Cheng et al, 2016;Sidler et al, 2017).…”

The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys

“…Furthermore, TGFβ has been identified as an effector molecule in CNT, since knockout of signaling components of the TGFβ pathway, or neutralizing this factor, protects from CsA nephrotoxic activity . In a recent publication, Chen et al proposed that TGFβ can induce Fn14 expression in dermal fibroblasts under some conditions, which could then contribute to fibrotic responses . We therefore sought to determine whether the Fn14‐inducing activity of CsA was driven indirectly via the induction and release of cell‐autonomous TGFβ.…”

Role of miR-24, Furin, and Transforming Growth Factor-β1 Signal Pathway in Fibrosis After Cardiac Infarction

“…A previous study reported the involvement of TGF-β1 in the fibrosis of multiple organs, such as heart, kidney, and liver [3]. TGF-β can activate transcriptional factor SMAD4, which further elevates Fn14 expression for the participation of extracellular matrix and activation of fibroblast [4]. TGF-β1 can facilitate the activation and collagen secretion of myocardial fibroblasts involved in the progression of cardiac fibrosis along with other risk factors [5].…”