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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 & AIMS:Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor ? (TGF-?) 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-? and PDGF signaling pathways. METHODS:We performed a transcriptomic comparison of HSCs treated with TGF-? or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators. RESULTS:Enhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-? 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-?-induced fibronectin, collagen 1?1, and ?-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-?-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 ?-smooth muscle actin/collagen protein assays. CONCLUSIONS:TGF-? 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-? as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-?-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).

Project description:Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor ? (TGF?) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGF? receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGF? inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGF?-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGF? pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGF? signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGF? and PDGF play a key role. Here, we show that a combined inhibition of TGF? and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGF?-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGF? and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGF? and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.

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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