LIM-Only Protein FHL2 Activates NF-κB Signaling in the Control of Liver Regeneration and Hepatocarcinogenesis
LIM-Only Protein FHL2 Activates NF-κB Signaling in the Control of Liver Regeneration and Hepatocarcinogenesis
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仅含LIM结构域的蛋白FHL2在肝脏再生和肝癌发生的调控中激活NF - κB信号通路
DOI：
10.1128/mcb.00105-13
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发表时间：
2013-08-01
影响因子：
5.3
通讯作者：
Wei, Yu
中科院分区：
文献类型：
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作者：
Dahan, Jennifer;Nouet, Yann;Wei, Yu
四条半LIM-Only Protein 2(FHL2)是许多信号通路中的重要调节因子。在本研究中，我们分析了FHL2在肝脏核因子-kappaB信号转导中的作用。我们证明，FHL2通过稳定蛋白来增强肿瘤坏死因子受体相关因子6(TRAF6)在转录激活核因子-kappaB靶标中的活性。TRAF6是FHL2的结合伙伴，是Toll样受体-核因子-kappaB途径的重要组成部分。在293-hTLR4/MD2-CD14细胞中，FHL2基因敲除可抑制脂多糖(LPS)诱导的核因子-kappaB的活性，从而调节炎性细胞因子的表达。事实上，FHL2(-/-)巨噬细胞在内毒素刺激后，肿瘤坏死因子和白介素6(IL-6)的产生显著减少。肿瘤坏死因子和白介素6是启动肝损伤后肝再生的关键细胞因子。肝部分切除后，FHL2(-/-)小鼠表现出对肿瘤坏死因子和白介素6的诱导作用减弱，肝细胞再生延迟。在肝脏中，核因子-kappa B信号协调肝细胞和肝免疫细胞之间的炎性串扰，从而促进化学肝癌的发生。我们发现，FHL2的缺失降低了对二乙基亚硝胺诱发肝癌的易感性，这与FHL2在核因子-kappaB信号中的激活作用有关。我们的研究结果表明，FHL2在肝再生和癌变过程中是核因子-kappaB活性的正调节因子，并强调了FHL2在肝细胞和肝免疫细胞中的重要性。
Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor kappa B (NF-kappa B) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-kappa B targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-kappa B pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-kappa B activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-kappa B signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-kappa B signaling. Our findings demonstrate FHL2 as a positive regulator of NF-kappa B activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.