Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844018355774 |
| _version_ | 1819071612541992960 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hiroshi Yokoyama |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T17:24:36Z |
| format | Article |
| id | doaj.art-3ee3824746ec4e2f980c2b9325dd3b04 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-12-21T17:24:36Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-3ee3824746ec4e2f980c2b9325dd3b042022-12-21T18:56:04ZengElsevierHeliyon2405-84402019-02-0152e01231Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver diseaseHiroshi Yokoyama0Takahiro Masaki1Ikuyo Inoue2Mariko Nakamura3Yoshihiro Mezaki4Chisato Saeki5Tsunekazu Oikawa6Masayuki Saruta7Hiroyuki Takahashi8Masahiro Ikegami9Hiroshi Hano10Kenichi Ikejima11Soichi Kojima12Tomokazu Matsuura13Department 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, JapanDepartment of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan; Corresponding author.Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, JapanDepartment of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, JapanDepartment of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanDepartment of Pathology, The Jikei University School of Medicine, Tokyo, JapanDepartment of Pathology, The Jikei University School of Medicine, Tokyo, JapanDepartment of Pathology, The Jikei University School of Medicine, Tokyo, JapanDepartment of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, JapanLiver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, Saitama, JapanDepartment of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, JapanTransforming 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.http://www.sciencedirect.com/science/article/pii/S2405844018355774Internal medicinePathology |
| spellingShingle | 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 Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease Heliyon Internal medicine Pathology |
| title | Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease |
| title_full | Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease |
| title_fullStr | Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease |
| title_full_unstemmed | Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease |
| title_short | Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease |
| title_sort | histological and biochemical evaluation of transforming growth factor β activation and its clinical significance in patients with chronic liver disease |
| topic | Internal medicine Pathology |
| url | http://www.sciencedirect.com/science/article/pii/S2405844018355774 |
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