The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity

被引:61
作者
Zhao, Shanmin [1 ,2 ]
Jiang, Jinghua [1 ]
Jing, Yingying [1 ]
Liu, Wenting [1 ]
Yang, Xue [1 ]
Hou, Xiaojuan [1 ]
Gao, Lu [1 ]
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
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
TNF-ALPHA; PATHWAY; CELLS; HEPATOTOXICITY; PROLIFERATION; INFLAMMATION; HEPATOCYTES; MECHANISMS; APOPTOSIS; BIOLOGY;
D O I
10.1038/s41419-020-2264-z
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:13
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共 49 条
  • [1] Mechanisms of cell death in acute liver failure
    Bantel, Heike
    Schulze-Osthoff, Klaus
    [J]. FRONTIERS IN PHYSIOLOGY, 2012, 3
  • [2] Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis
    Basu, S
    Totty, NF
    Irwin, MS
    Sudol, M
    Downward, J
    [J]. MOLECULAR CELL, 2003, 11 (01) : 11 - 23
  • [3] Regulation of liver regeneration by growth factors and cytokines
    Boehm, Friederike
    Koehler, Ulrike A.
    Speicher, Tobias
    Werner, Sabine
    [J]. EMBO MOLECULAR MEDICINE, 2010, 2 (08) : 294 - 305
  • [4] A Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial of Etanercept in the Treatment of Alcoholic Hepatitis
    Boetticher, Nicholas C.
    Peine, Craig J.
    Kwo, Paul
    Abrams, Gary A.
    Pateo, Tushar
    Aqel, Bashar
    Boardman, Lisa
    Gores, Gregory J.
    Harmsen, William S.
    McClain, Craig J.
    Kamath, Patrick S.
    Shah, Vijay H.
    [J]. GASTROENTEROLOGY, 2008, 135 (06) : 1953 - 1960
  • [5] Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche
    Bonnardel, Johnny
    T'Jonck, Wouter
    Gaublomme, Djoere
    Browaeys, Robin
    Scott, Charlotte L.
    Martens, Liesbet
    Vanneste, Bavo
    De Prijck, Sofie
    Nedospasov, Sergei A.
    Kremer, Anna
    Van Hamme, Evelien
    Borghgraef, Peter
    Toussaint, Wendy
    De Bleser, Pieter
    Mannaerts, Inge
    Beschin, Alain
    van Grunsven, Leo A.
    Lambrecht, Bart N.
    Taghon, Tom
    Lippens, Saskia
    Elewaut, Dirk
    Saeys, Yvan
    Guilliams, Martin
    [J]. IMMUNITY, 2019, 51 (04) : 638 - 654
  • [6] Regulation of tumour necrosis factor signalling: live or let die
    Brenner, Dirk
    Blaser, Heiko
    Mak, Tak W.
    [J]. NATURE REVIEWS IMMUNOLOGY, 2015, 15 (06) : 362 - 374
  • [7] Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice
    Chiu, H
    Gardner, CR
    Dambach, DM
    Durham, SK
    Brittingham, JA
    Laskin, JD
    Laskin, DL
    [J]. TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 193 (02) : 218 - 227
  • [8] TNF--Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells
    Choi, Hyun-Jung
    Kim, Na-Eun
    Kim, Byeong Mo
    Seo, Miran
    Heo, Ji Hoe
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2018, 19 (11)
  • [9] Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine
    de Andrade, Kivia Queiroz
    Moura, Fabiana Andrea
    dos Santos, John Marques
    Pimentel de Araujo, Orlando Roberto
    de Farias Santos, Juliana Celia
    Fonseca Goulart, Marilia Oliveira
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2015, 16 (12): : 30269 - 30308
  • [10] LATS2 induced by TNF-alpha and inhibited cell proliferation and invasion by phosphorylating YAP in oral squamous cell carcinoma
    Dong, Cong
    Wei, Kui-Jie
    Zhang, Wen-Bin
    Sun, Hao
    Pan, Hong-Ya
    Zhang, Lei
    [J]. JOURNAL OF ORAL PATHOLOGY & MEDICINE, 2015, 44 (06) : 475 - 481