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

Abstract

Uncontrolled activation of transforming growth factor (TGF)-beta results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-beta 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 alpha(v) integrin-mediated activation of TGF-beta. Del-1 bound to alpha(v)beta(6) integrin, an important activator of TGF-beta, and inhibited the binding of alpha(v)beta(6) integrin to the latency-associated peptide (LAP), thereby suppressing alpha(v) integrin-mediated activation of TGF-beta. Lack of Del-1 increased colocalization of alpha(v) integrin and LAP in the lungs, which was reversed by Del-1 supplementation. The crucial role of Del-1 in regulating TGF-beta activity was recapitulated in a mouse model of fibrosis using an adenovirus expressing inactive TGF-beta 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-beta activation and a potential anti-fibrotic factor.