Redox-mediated activation of latent transforming growth factor-beta 1.

Abstract

Transforming growth factor beta 1 (TGF beta) is a multifunctional cytokine that orchestrates response to injury via ubiquitous cell surface receptors. The biological activity of TGF beta is restrained by its secretion as a latent complex (LTGF beta) such that activation determines the extent of TGF beta activity during physiological and pathological events. TGF beta action has been implicated in a variety of reactive oxygen-mediated tissue processes, particularly inflammation, and in pathologies such as reperfusion injury, rheumatoid arthritis, and atherosclerosis. It was recently shown to be rapidly activated after in vivo radiation exposure, which also generates reactive oxygen species (ROS). In the present studies, the potential for redox-mediated LTGF beta activation was investigated using a cell-free system in which ROS were generated in solution by ionizing radiation or metal ion-catalyzed ascorbate reaction. Irradiation (100 Gray) of recombinant human LTGF beta in solution induced 26% activation compared with that elicited by standard thermal activation. Metal-catalyzed ascorbate oxidation elicited extremely efficient recombinant LTGF beta activation that matched or exceeded thermal activation. The efficiency of ascorbate activation depended on ascorbate concentrations and the presence of transition metal ions. We postulate that oxidation of specific amino acids in the latency-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 which 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. LTGF beta redox sensitivity is presumably directed toward recovery of homeostasis; however, oxidation may also be a mechanism of LTGF beta activation that can be deleterious during disease mechanisms involving chronic ROS production.

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

“…Several pieces of evidence have implicated the TGF-␤ system as a major etiological agent in the pathogenesis of cardiac fibrosis, including type III collagen overexpression and LV remodeling in AMI. 8,35,36 Because latent TGF-␤ can be activated in vitro on oxidative stress generation, 39 anti-oxidative properties of PEDF could contribute directly to its antifibrotic effects in our AMI model as well.…”

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

“…Ascorbate, in the presence of transition metal ions, is an extremely efficient activator of latent TGF␤, converting it to its active form (39). Active TGF␤ plays a key role in osteophyte formation (40).…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Tumor-secreted TGFβ is usually sequestered to the extracellular matrix as an inactive complex, and becomes activated through enzymes such as neutrophil-derived elastase and matrix metalloproteinase (MMP)-9, or expression of α v β 6 integrin [78]. In addition, reactive oxygen free radicals produced by activated neutrophils can activate latent TGFβ [81]. Thus, activated neutrophils, through production of elastase, MMP-9 and ROS, may contribute to TGFβ-mediated immunosuppression, a mechanism that may drive a negative feedback that prevents excessive immune responses.…”

“…T cells further increase the activity of neutrophils through secretion of IFNγ. The increase in oxygen radicals have additional effects, such as suppression of T cell responses [278,384], activation of TGFβ [81], and induction of GMP-140 (P-Selectin) expression on the surface of endothelial cells, leading to enhanced neutrophil adherence and activity [385]. The activation of TGFβ suppresses excessive neutrophil function, and may polarize them into N2 neutrophils [13].…”