Latent TGF-β1 Activation by Platelets

Platelets are a major source of transforming growth factor-β1 (TGF-β1) in the circulation as they release latent growth factor in response to activation. We report here that human platelets, when stimulated with thrombin, activated a significant proportion of the latent TGF-β released. Latent TGF-β activation was independent of cytokine release, since activation was delayed compared to platelet degranulation. Activation occured in releasates and did not require the continuous presence of platelets. Classical mechanisms of latent TGF-β activation were not involved, since activation was not affected by gene deletion and/or inhibitors of the known TGF-β activators/co-factors, thrombospondin-1 (TSP-1), mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR), plasminogen/plasmin, or several other candidate proteases. In contrast, latent TGF-β activation was significantly inhibited by the furin inhibitors, decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone and L-hexaarginine. We show that platelets contain a furin-like enzyme which is released upon platelet activation. We conclude that, following activation, platelets release and activate latent TGF-β1 via mechanisms involving the release and activity of a furin-like proprotein convertase. This novel mechanism of latent TGF-β activation might represent an important mediator and therapeutic target of platelet TGF-β1 functions, for example, in early wound repair, fibrosis, or arteriosclerosis. © 2003 Wiley-Liss, Inc.