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

ABSTRACT: Previous studies have shown that tumor necrosis factor (TNF)-? is a mediator of hepatotoxicity in liver injury. Moreover, TNF-? has also been reported to have a protective effect in liver regeneration, yet the function of TNF-? during liver injury remains controversial. Here, we report that the concentration of TNF-? determines its functions. High concentrations of TNF-? could aggravate LPS-induced liver injury. However, the TNF-? level was unchanged during APAP-induced liver injury, which exerted a protective effect. We expected that the concentration of TNF-? may affect its function. To test this hypothesis, TNF-?-/- rats or hepatocyte cells were treated with different concentrations of TNF-?. We found low TNF-? could reduce the levels of ALT and AST in the plasma of TNF-?-/- rats and promote the proliferation of hepatocyte cells. However, the levels of ALT and AST increased gradually with increasing TNF-? concentration after reaching the lowest value. Moreover, we showed that TNF-? affects the cell proliferation and cell death of hepatocytes by regulating Yap activity. Low TNF-? promoted Yap1 nuclear translocation, triggering the proliferation of hepatocytes. However, high TNF-? 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-? is an important factor affecting its function in liver injury, which may provide a reference for the clinical treatment of liver injury.

SUBMITTER: Zhao S

PROVIDER: S-EPMC6985193 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Zhao Shanmin S Jiang Jinghua J Jing Yingying Y Liu Wenting W Yang Xue X Hou Xiaojuan X Gao Lu L Wei Lixin L

Cell death & disease 20200127 1

Previous studies have shown that tumor necrosis factor (TNF)-α is a mediator of hepatotoxicity in liver injury. Moreover, TNF-α has also been reported to have a protective effect in liver regeneration, yet the function of TNF-α during liver injury remains controversial. Here, we report that the concentration of TNF-α determines its functions. High concentrations of TNF-α could aggravate LPS-induced liver injury. However, the TNF-α level was unchanged during APAP-induced liver injury, which exert ...[more]

PMID: 31988281

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Project description:Background & aimsTumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.MethodsWe searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.ResultsThe drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.ConclusionsAcute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

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

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

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