Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease

Abstract Transforming growth factor-β (TGF-β) is a key driver for liver fibrogenesis. TGF-β must be activated in order to function. Plasma kallikrein (PLK) is a TGF-β activator that cleaves the latency-associated protein (LAP) between arginine 58 and lysine 59 residues and releases active TGF-β from the latent TGF-β-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine 58 (R 58 /LAP-DPs) and beginning from lysine 59 (L 59 /LAP-DPs), reflects PLK-dependent TGF-β activation. However, the significance and details of TGF-β activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-β activation in patients by detecting R 58 and L 59 /LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R 58 /LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L 59 /LAP-DP concentration. R 58 /LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R 58 /LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L 59 /LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L 59 /LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-β activation occurs in the early stages of fibrosis and that its unique surrogate markers, R 58 and L 59 /LAP-DPs, are useful for monitoring the clinical course of CLD.