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Del-1, an Endogenous Inhibitor of TGF-? Activation, Attenuates Fibrosis.

ABSTRACT: Uncontrolled activation of transforming growth factor (TGF)-? results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-? signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibrosis in mice by inhibiting ?v integrin-mediated activation of TGF-?. Del-1 bound to ?v?6 integrin, an important activator of TGF-?, and inhibited the binding of ?v?6 integrin to the latency-associated peptide (LAP), thereby suppressing ?v integrin-mediated activation of TGF-?. Lack of Del-1 increased colocalization of ?v integrin and LAP in the lungs, which was reversed by Del-1 supplementation. The crucial role of Del-1 in regulating TGF-? activity was recapitulated in a mouse model of fibrosis using an adenovirus expressing inactive TGF-?1. Del-1 supplementation improved the pathological characteristics of the mice and reduced mortality. Thus, we propose that Del-1 is a negative regulator of TGF-? activation and a potential anti-fibrotic factor.

SUBMITTER: Kim DY

PROVIDER: S-EPMC7018852 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Del-1, an Endogenous Inhibitor of TGF-β Activation, Attenuates Fibrosis.

Kim Dong-Young DY Lee Seung-Hwan SH Fu Yan Y Jing Feifeng F Kim Won-Young WY Hong Sang-Bum SB Song Jung-A JA Choe Han H Ryu Hyun Jin HJ Kim Minjung M Lim Dahae D Kim Min-Seon MS Yun Chae-Ok CO Lee Taewon T Hyun Hoon H Choi Eun Young EY

Frontiers in immunology 20200207

Uncontrolled activation of transforming growth factor (TGF)-β results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-β signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibrosis in mice by inhibiting αv integrin-mediated activation of TGF-β. Del-1 bound to αvβ6 integrin, an important activator of TGF-β, and inhibited th ...[more]

PMID: 32117240

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Project description:Background & aimsTransdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways.MethodsWe performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators.ResultsEnhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β-induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β-treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays.ConclusionsTGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β-treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606).

Dataset Information

Del-1, an Endogenous Inhibitor of TGF-? Activation, Attenuates Fibrosis.

Publications

Del-1, an Endogenous Inhibitor of TGF-β Activation, Attenuates Fibrosis.

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