The recombinant proregion of transforming growth factor β1 (Latency-associated peptide) inhibits active transforming growth factor β1 in transgenic mice

All three isoforms of transforming growth factors β (TGF-β1, TGF-β2, and TGF-β3) 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-β1 was expressed in a baculovirus expression system and purified to homogeneity. In vitro assays of growth inhibition and gene induction mediated by TGF-β demonstrate that recombinant TGF-β1 LAP is a potent inhibitor of the activities of TGF-β1, -β2, and -β3. Effective dosages of LAP for 50% neutralization of TGF-β activities range from 4.7- to 80-fold molar excess depending on the TGF-β isoform and activity examined. Using ¹²⁵I-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 8-fold lower. In transgenic mice with elevated hepatic levels of bioactive TGF-β1, treatment with recombinant LAP completely reverses suppression of the early proliferative response induced by TGF-β1 in remnant livers after partial hepatectomy. The results suggest that recombinant LAP is a potent inhibitor of bioactive TGF-β 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-β.