| First Author | Ahamed J | Year | 2008 |
| Journal | Blood | Volume | 112 |
| Issue | 9 | Pages | 3650-60 |
| PubMed ID | 18544680 | Mgi Jnum | J:141786 |
| Mgi Id | MGI:3819736 | Doi | 10.1182/blood-2008-04-151753 |
| Citation | Ahamed J, et al. (2008) In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-beta1. Blood 112(9):3650-60 |
| abstractText | 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. |
