Post translational activation of latent transforming growth factor beta (L-TGF-beta): clinical implications

Transforming growth factor-betas (TGF-betas) are multifunctional cytokines that exist in 3 isoforms in mammals. The TGF-betas are ubiquitously expressed and all isoforms are secreted as biologically inactive precursors called latent TGF-beta (L-TGF-beta). L-TGF-betas are generally not effective molecules because they are unable to interact with their receptors. However, the removal of or conformational change of the precursor protein called the latency associated peptide (LAP) results in the generation of biologically active TGF-beta. In vitro active TGF-beta has many biological effects but from a clinical point of view one of the most recognized associations of aberrant TGF-beta production is with diseases characterized by enhanced connective tissue synthesis. Recently a number of observations in the context of fibrotic disorders suggest mechanisms of activation of L-TGF-beta1 in vivo. The recognition of mechanisms that activate L-TGF-beta1 in vivo offers the possibility of interfering with the activation of L-TGF-beta1 for therapeutic purposes.