In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-beta1.

Abstract:

:Transforming growth factor-beta1 (TGF-beta1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-beta1 as other cells and secrete it as an inactive (latent) form in complex with latency-associated peptide (LAP), which is disulfide bonded via Cys33 to latent TGF-beta binding protein 1 (LTBP-1). Little is known about how latent TGF-beta1 becomes activated in vivo. Here we show that TGF-beta1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thiol-disulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-beta1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-beta1 contained in complex with only LAP could not be activated by stirring when studied as either a recombinant purified protein complex or in the platelet releasates or sera of mice engineered to contain an LAP C33S mutation. Release and activation of latent TGF-beta1 in vivo was demonstrated in a mouse model 5 minutes after thrombus formation. These data potentially provide a novel mechanism for in vivo activation of TGF-beta1.

journal_name

Blood

journal_title

Blood

authors

Ahamed J,Burg N,Yoshinaga K,Janczak CA,Rifkin DB,Coller BS

doi

10.1182/blood-2008-04-151753

subject

Has Abstract

pub_date

2008-11-01 00:00:00

pages

3650-60

issue

9

eissn

0006-4971

issn

1528-0020

pii

blood-2008-04-151753

journal_volume

112

pub_type

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