REDOX-MEDIATED ACTIVATION OF LATENT TRANSFORMING GROWTH-FACTOR-BETA-1

Transforming growth factor beta 1 (TGF beta) is a multifunctional cyto kine that orchestrates response to injury via ubiquitous cell surface receptors. The biological activity of TGF beta is restrained by its se cretion as a latent complex (LTGF beta) such that activation determine s the extent of TGF beta activity during physiological and pathologica l events, TGF beta action has been implicated in a variety of reactive oxygen-mediated tissue processes, particularly inflammation, and in p athologies such as reperfusion injury, rheumatoid arthritis, and ather osclerosis. It was recently shown to be rapidly activated after in viv o radiation exposure, which also generates reactive oxygen species (RO S). In the present studies, the potential for redox-mediated LTGF beta activation was investigated using a cell-free system in which ROS wer e generated in solution by ionizing radiation or metal ion-catalyzed a scorbate reaction, Irradiation (100 Gray) of recombinant human LTGF be ta in solution induced 26% activation compared with that elicited by s tandard thermal activation, Metal-catalyzed ascorbate oxidation elicit ed extremely efficient recombinant LTGF beta activation that matched o r exceeded thermal activation. The efficiency of ascorbate activation depended on ascorbate concentration and the presence of transition met al ions. We postulate that oxidation of specific amino acids in the la tency-conferring peptide leads to a conformation change in the latent complex that allows release of TGF beta. Oxidative activation offers a novel route for the involvement of TGF beta in tissue processes in wh ich ROS are implicated and endows LTGF beta with the ability to act as a sensor of oxidative stress and, by releasing TGF beta, to function as a signal for orchestrating the response of multiple cell types. LTG F beta redox sensitivity is presumably directed toward recovery of hom eostasis; however, oxidation may also be a mechanism of LTGF beta acti vation that can be deleterious during disease mechanisms involving chr onic ROS production.