The recombinant proregion of transforming growth factor beta 1 (Latency-associated peptide) inhibits active transforming growth factor beta 1 in transgenic mice

All three isoforms of transforming growth factors beta (TGF-beta 1, TGF-beta 2, and TGF-beta 3) are secreted as latent complexes and activated extracellularly, leading to the release of the mature cytokines from their noncovalently associated proregions, also known as latency-associated peptides (LAPs), The LAP region of TGF-beta 1 was expressed in a baculovirus expression system and purified to homogeneity. In vitro assays of growth inhibition and gene induction mediated by TGF-beta demonstrate that recombinant TGF-beta 1 LAP is a potent inhibitor of the activities of TGF-beta 1, -beta 2, and -beta 3, Effective dosages of LAP for 50% neutralization of TGF-beta activities range from 4.7- to 80-fold molar excess depending on the TGF-beta isoform and activity examined. Using (125)-labeled LAP, we show that the intraperitoneal application route is effective for systemic administration of LAP, Comparison of concentrations of LAP in tissues shows a homogenous pattern in most organs with the exception of heart and muscle, in which levels of LAP are 4- to I-fold lower, In transgenic mice with elevated hepatic levels of bioactive TGF-beta 1, treatment with recombinant LAP completely reverses suppression of the early proliferative response induced by TGF-beta 1 in remnant livers after partial hepatectomy. The results suggest that recombinant LAP is a potent inhibitor of bioactive TGF-beta both in vitro and in vivo, after intraperitoneal administration, Recombinant LAP should be a useful tool for novel approaches to study and therapeutically modulate pathophysiological processes mediated by TGF-beta.