Detection and regulation of hepatic diseases targeting TGF-β activation reaction.

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Transforming growth factor (TGF)-β, a 25 kD dimeric polypeptide playing a pivotal role in the pathogenesis of liver diseases, is produced as a high molecular weight latent form, and activated by plasmin (PLN) and plasma kallikrein (PLK) during pathogenesis of liver diseases. Blockage of the activation reaction with low molecular weight protease inhibitors prevented the development of the diseases in animal models. Based upon these findings, here, we found that(1) PLN and PLK cleaved between K56-L57 and R58-L59 in LAP portion of human latent TGF-β1, respectively. We produced antibodies that specifically recognize the neo-epitopes formed by protease degradation, namely the cut ends of each cleavage site. The anti-R58 antibodies strongly stained liver sections from patients with fulminant hepatitis.(2) The anti-L59 antibodies were successively used to establish ELISA to detect LAP degradation fragments in serum of mouse impaired liver regeneration model as well as rat CCl4 and bile duct ligation hepatic fibrosis models, showing a good correlation with serum transamidase levels and hepatic hydroxyproline levels.(3) Decoy peptides containing the cleavage sites blocked the activation of TGF-β in the hepatic stellate cells and improved hepatic regeneration in the mouse model.(4) In scleroderma TGF-β2 is the main isoform and MMP, but not PLN and PLK, appeared to be involved in its activation reaction.(5) CXZ, which has been shown to suppress phosphorylation of Smad, successfully improved hepatic regeneration in the mouse model.These results suggest that a PLN/PLK-dependent activation reaction occurs around hepatic stellate cells to produce active TGF-β, which may induce fibrosis and inhibit the proliferation of hepatocytes, thereby addressing a potential use for decoy peptides in hepatitis therapy. These results also suggest a potential usage of a LAP degradate as a novel biomarker for liver fibrosis.