Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice
| Autor: | Eiko Saijou, Michitaka Matsuda, Minoru Tanaka, Hitoshi Okochi, Atsushi Miyajima, Naoko Miyata, Shinya Tsurusaki |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Liver Cirrhosis
Male 0301 basic medicine medicine.medical_treatment Inflammation Oncostatin M Biology Risk Assessment Statistics Nonparametric Mice Random Allocation 03 medical and health sciences 0302 clinical medicine Fibrosis Hepatic Stellate Cells medicine Animals Humans Cells Cultured Chromatography High Pressure Liquid TIMP1 Mice Knockout Analysis of Variance Hepatology Growth factor Monocyte fungi medicine.disease Liver Regeneration Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Knockout mouse Immunology Hepatocytes biology.protein Cancer research Hepatic stellate cell medicine.symptom Biomarkers |
| Zdroj: | Hepatology. 67:296-312 |
| ISSN: | 1527-3350 0270-9139 |
| DOI: | 10.1002/hep.29421 |
| Popis: | Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors, such as transforming growth factor-β and platelet-derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence-activated cell sorting analyses using OSM-HTVi and OSM knockout mice have revealed that bone-marrow–derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. Conclusion: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (Hepatology 2018;67:296-312). |
| Databáze: | OpenAIRE |
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