Byproducts of
cytokine activation are sometimes useful as surrogate
biomarkers for monitoring
cytokine generation in patients.
Transforming growth factor (TGF)-β plays a pivotal role in pathogenesis of hepatic
fibrosis. TGF-β is produced as part of an inactive latent complex, in which the
cytokine is trapped by its propeptide, the latency-associated
protein (LAP). Therefore, to exert its
biological activity, TGF-β must be released from the latent complex. Several
proteases activate latent TGF-β by cutting LAP. We previously reported that
Camostat Mesilate, a broad spectrum
protease inhibitor, which is especially potent at inhibiting
plasma kallikrein (PLK), prevented
liver fibrosis in the porcine serum-induced
liver fibrosis model in rats. We suggested that PLK may work as an activator of latent TGF-β during the pathogenesis of
liver diseases in the animal models. However, it remained to be elucidated whether this activation mechanism also functions in fibrotic liver in patients. Here, we report that PLK cleaves LAP between R(58) and L(59) residues. We have produced
monoclonal antibodies against two degradation products of LAP (LAP-DP) by PLK, and we have used these specific
antibodies to immunostain LAP-DP in liver tissues from both fibrotic animals and patients. The N-terminal side LAP-DP ending at R(58) (R(58) LAP-DP) was detected in liver tissues, while the C-terminal side LAP-DP beginning at L(59) (L(59) LAP-DP) was not detectable. The R(58) LAP-DP was seen mostly in α-smooth muscle actin-positive activated stellate cells. These data suggest for the first time that the occurrence of a PLK-dependent TGF-β activation reaction in patients and indicates that the LAP-DP may be useful as a
surrogate marker reflecting PLK-dependent TGF-β activation in fibrotic liver both in animal models and in patients.