Latent TGF-beta1 activation by platelets.
Platelets are a major source of transforming growth factor-beta1 (TGF-beta1) 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-beta released. Latent TGF-beta 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-beta activation were not involved, since activation was not affected by gene deletion and/or inhibitors of the known TGF-beta 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-beta 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-beta1 via mechanisms involving the release and activity of a furin-like proprotein convertase. This novel mechanism of latent TGF-beta activation might represent an important mediator and therapeutic target of platelet TGF-beta1 functions, for example, in early wound repair, fibrosis, or arteriosclerosis.
Department of Cancer Research, Fachklinik Hornheide, University of Münster, Münster, Germany.
Robert
R
Blakytny
Anna
A
Ludlow
Gail E M
GE
Martin
Grenham
G
Ireland
Leif R
LR
Lund
Mark W J
MW
Ferguson
Georg
G
Brunner
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D045683:Furin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D004791:Enzyme Inhibitors; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D045683:Furin