Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine with important roles in inflammation, wound repair, and cancer. Cells secrete TGF-beta as a latent protein complex, consisting of disulfide-bonded homodimers of growth factor and latency-associated propeptide. Latency regulates extracellular TGF-beta action by controlling the levels of active growth factor available. We report here that active and latent TGF-beta were inactivated in vitro by reduction of the growth factor dimer under physiological conditions. We also demonstrate that the latency-associated propeptide has chaperone-like activity and partially protects TGF-beta from inactivation. TGF-beta inactivation occurred upon incubation with the physiological redox agents, cysteine, homocysteine, and reduced glutathione. Inactivation was temperature- and dose-dependent. While inactivation by physiological concentrations of redox agents was partial at 37 degrees C, active and latent TGF-beta were completely inactivated by raising the temperature in the presence of the redox agents. The mechanism of TGF-beta inactivation involved the generation of biologically inactive growth factor monomer and required the presence of free thiol groups, since thiol blockers protected TGF-beta from reduction. We conclude that non-enzymatic redox reactions may be involved in the regulation of extracellular TGF-beta activity. This might be of particular relevance in wound repair (e.g. in burns), as a mechanism protecting from excess TGF-beta activity, as well as in conditions involving redox dysregulation, such as reperfusion injury of the heart, Alzheimer's disease, and cancer.