Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury

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• 作者：Junfei Hu¹ ; ² ; ^&dagger ; ; Xue-Hai Zhu³ ; ^&dagger ; ; Xiao-Jing Zhang⁴ ; ^&dagger ; ; Pi-Xiao Wang¹ ; ² ; Ran Zhang⁵ ; Peng Zhang¹ ; ² ; Guang-Nian Zhao¹ ; ² ; Lu Gao⁶ ; Xiao-Fei Zhang⁷ ; Song Tian¹ ; ² ; Hongliang Li¹ ; ² ; ^{lihl@whu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：I/R ; ischemia/reperfusion ; TRAF3 ; tumor necrosis factor receptor (TNFR)-associated factor 3 ; KO ; knockout ; TG ; transgenic ; H/R ; hypoxia/reoxygenation ; ROS ; reactive oxygen species ; ALT ; alanine amino transferase ; AST ; aspartate amino transferase ; TNF-α ; tumor necrosis factor-α ; IL-1β ; interleukin-1β ; MCP-1 ; monocyte chemoattractant protein-1 ; CXCL-1 ; chemokine (C-X-C motif) ligand 1 ; LDH ; lactate dehydrogenase ; NTG ; non-transgenic ; ERK ; extracellular signal-regulated kinase ; JNK ; c-Jun-N-termina
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：64
• 期：1
• 页码：146-159
• 全文大小：5765 K

文摘

The hallmarks of hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, include severe cell death and inflammatory responses that contribute to early graft failure and a higher incidence of organ rejection. Unfortunately, effective therapeutic strategies are limited. Tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 3 transduces apoptosis and/or inflammation-related signaling pathways to regulate cell survival and cytokine production. However, the role of TRAF3 in hepatic I/R-induced liver damage remains unknown.

Methods

Hepatocyte- or myeloid cell-specific TRAF3 knockdown or transgenic mice were subjected to an I/R model in vivo, and in vitro experiments were performed by treating primary hepatocytes from these mice with hypoxia/reoxygenation stimulation. The function of TRAF3 in I/R-induced liver damage and the potential underlying mechanisms were investigated through various phenotypic analyses and biological approaches.

Results

Hepatocyte-specific, but not myeloid cell-specific, TRAF3 deficiency reduced cell death, inflammatory cell infiltration, and cytokine production in both in vivo and in vitro hepatic I/R models, whereas hepatic TRAF3 overexpression resulted in the opposite effects. Mechanistically, TRAF3 directly binds to TAK1, which enhances the activation of the downstream NF-κB and JNK pathways. Importantly, inhibition of TAK1 almost completely reversed the TRAF3 overexpression-mediated exacerbation of I/R injury.

Conclusions

TRAF3 is a novel hepatic I/R mediator that promotes liver damage and inflammation via TAK1-dependent activation of the JNK and NF-κB pathways. Inhibition of hepatic TRAF3 may represent a promising approach to protect the liver against I/R injury-related diseases.