期刊
BLOOD
卷 112, 期 9, 页码 3650-3660出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-04-151753
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资金
- National Heart, Lung and Blood Institute [19278]
- National Cancer Institute [034282]
- Philip Morris USA
- Clinical and Translational Science Award [5UL1RR024143]
- National Center for Research Resources (NIH)
- New York City Community Trust (NYCT)
- Glorney-Raisbach Research Foundation Fellowship Award
- Uehara Foundation Fellowship ( Tokyo, Japan
- K.Y.)
- Stony Brook University ( Stony Brook, NY)
Transforming growth factor-beta 1 (TGF-beta 1) has potent physiologic and pathologic effects on a variety of cell types at subnanomolar concentrations. Platelets contain 40 times as much TGF-beta 1 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-beta 1 becomes activated in vivo. Here we show that TGF-beta 1 released from platelets or fibroblasts undergoes dramatic activation when subjected to stirring or shear forces, providing a potential mechanism for physiologic control. Thioldisulfide exchange appears to contribute to the process based on the effects of thiol-reactive reagents and differences in thiol labeling of TGF-beta 1 before and after stirring or shear. Activation required the presence of LTBP, as TGF-beta 1 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-beta 1 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-beta 1. (Blood. 2008; 112: 3650-3660)
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