The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity
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作者:
Zhao, Shanmin
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Second Mil Med Univ, Lab Anim Ctr, Shanghai 200433, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Zhao, Shanmin
[1
,2
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Jiang, Jinghua
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Jiang, Jinghua
[1
]
Jing, Yingying
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Jing, Yingying
[1
]
Liu, Wenting
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Liu, Wenting
[1
]
Yang, Xue
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Yang, Xue
[1
]
Hou, Xiaojuan
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Hou, Xiaojuan
[1
]
Gao, Lu
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Gao, Lu
[1
]
Wei, Lixin
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Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R ChinaSecond Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
Wei, Lixin
[1
]
机构:
[1] Second Mil Med Univ, Affiliated Hosp 3, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
[2] Second Mil Med Univ, Lab Anim Ctr, Shanghai 200433, Peoples R China
Previous studies have shown that tumor necrosis factor (TNF)-alpha is a mediator of hepatotoxicity in liver injury. Moreover, TNF-alpha has also been reported to have a protective effect in liver regeneration, yet the function of TNF-alpha during liver injury remains controversial. Here, we report that the concentration of TNF-alpha determines its functions. High concentrations of TNF-alpha could aggravate LPS-induced liver injury. However, the TNF-alpha level was unchanged during APAP-induced liver injury, which exerted a protective effect. We expected that the concentration of TNF-alpha may affect its function. To test this hypothesis, TNF-alpha (-/-) rats or hepatocyte cells were treated with different concentrations of TNF-alpha. We found low TNF-alpha could reduce the levels of ALT and AST in the plasma of TNF-alpha (-/-) rats and promote the proliferation of hepatocyte cells. However, the levels of ALT and AST increased gradually with increasing TNF-alpha concentration after reaching the lowest value. Moreover, we showed that TNF-alpha affects the cell proliferation and cell death of hepatocytes by regulating Yap activity. Low TNF-alpha promoted Yap1 nuclear translocation, triggering the proliferation of hepatocytes. However, high TNF-alpha triggered the phosphorylation and inactivation of Yap1, preventing its nuclear import and consequently promoting cell death. Collectively, our findings provide novel evidence that the concentration of TNF-alpha is an important factor affecting its function in liver injury, which may provide a reference for the clinical treatment of liver injury.
机构:
Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Kim, Na-Eun
Kim, Byeong Mo
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Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Kim, Byeong Mo
Seo, Miran
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Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Seo, Miran
Heo, Ji Hoe
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Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Yonsei Univ, Coll Med, Dept Neurol, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
机构:
Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Kim, Na-Eun
Kim, Byeong Mo
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机构:
Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Kim, Byeong Mo
Seo, Miran
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机构:
Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Seo, Miran
Heo, Ji Hoe
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机构:
Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea
Yonsei Univ, Coll Med, Dept Neurol, 50 Yonsei Ro, Seoul 03722, South KoreaYonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, 50 Yonsei Ro, Seoul 03722, South Korea