The integrin αvβ6 binds and activates latent TGFβ1 : A mechanism for regulating pulmonary inflammation and fibrosis

Summary The mechanisms involved in activating latent TGFb are not fully understood, but recently there has been Transforming growth factor b (TGFb) family members important progress in this area. Plasmin can activate are secreted in inactive complexes with a latency- latent TGFb in cell-free systems (Lyons et al., 1990) and associated peptide (LAP), a protein derived from the in cell culture (Sato et al., 1990). However, plasminogen N-terminal region of the TGFb gene product. Extracel- knockout mice display none of the pathologic features lular activation of these complexes is a critical but of TGFb knockout mice, suggesting that plasmin is unincompletely understood step in regulation of TGFb likely to be the only molecule activating TGFb. Reactive function in vivo. We show that TGFb1 LAP is a ligand oxygen species can activate TGFb in vitro (Barcellosfor the integrin avb6 and that avb6-expressing cells Hoff and Dix, 1996), and radiation treatment appears induce spatially restricted activation of TGFb1. This able to activate TGFb in vivo via this mechanism (Barfinding explains why mice lacking this integrin develop cellos-Hoff et al., 1994). Thrombospondin (TSP) 1 can exaggerated inflammation and, as we show, are pro- activate TGFb by binding to a defined site on LAP and tected from pulmonary fibrosis. These data identify a inducing a conformational change in the latent complex; novel mechanism for locally regulating TGFb1 function TGFb is then bound to TSP1 in an active state (Schultzin vivo by regulating expression of the avb6 integrin. Cherry and Murphy-Ullrich, 1993; Schultz-Cherry et al.,