Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease
Hiroshi Yokoyama,
Takahiro Masaki,
Ikuyo Inoue,
Mariko Nakamura,
Yoshihiro Mezaki,
Chisato Saeki,
Tsunekazu Oikawa,
Masayuki Saruta,
Hiroyuki Takahashi,
Masahiro Ikegami,
Hiroshi Hano,
Kenichi Ikejima,
Soichi Kojima,
Tomokazu Matsuura
Affiliations
Hiroshi Yokoyama
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Takahiro Masaki
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan; Corresponding author.
Ikuyo Inoue
Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, Japan
Mariko Nakamura
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
Yoshihiro Mezaki
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
Chisato Saeki
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Tsunekazu Oikawa
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Masayuki Saruta
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Hiroyuki Takahashi
Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
Masahiro Ikegami
Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
Hiroshi Hano
Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
Kenichi Ikejima
Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Soichi Kojima
Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, Japan
Tomokazu Matsuura
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
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 arginine58 and lysine59 residues and releases active TGF-β from the latent TGF-β-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine58 (R58/LAP-DPs) and beginning from lysine59 (L59/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 R58 and L59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L59/LAP-DP concentration. R58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L59/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, R58 and L59/LAP-DPs, are useful for monitoring the clinical course of CLD.
