Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8(+) T cells in normal and cirrhotic livers.
Hepatocyte growth factor-mediated apoptosis mechanisms of cytotoxic CD8(+) T cells in normal and cirrhotic livers.
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正常和肝硬化肝脏中肝细胞生长因子介导的细胞毒性CD8 T细胞凋亡机制
DOI：
10.1038/s41420-023-01313-4
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发表时间：
2023-01-19
影响因子：
7
通讯作者：
Bai, Lianhua
中科院分区：
文献类型：
--
作者：
Chen, Quanyu;Yan, Min;Lin, Heng;Lai, Jiejuan;Yang, Zhiqing;Hu, Deyu;Deng, Yuanyu;Shi, Saiyu;Shuai, Ling;Zhang, Leida;Zhang, Hongyu;Bai, Lianhua
肝内干/祖细胞和细胞毒性CD 8 + T细胞（CD 8 + T细胞）在肝硬化的肝脏经历凋亡，这可能促进癌症的进展。在这里，我们报告，肝细胞生长因子（HGF）信号在促进正常和受损的肝脏CD 8 + T细胞Fas介导的凋亡中起着重要的作用，通过其唯一的受体，c-Met。除了与HGF结合外，c-Met还与Fas结合形成复合物。使用二乙基亚硝胺（DEN）诱导的肝纤维化/肝硬化小鼠模型，免疫染色，和末端脱氧核苷酸转移酶（TdT）dUTP缺口末端标记（TUNEL）染色，我们发现，肝细胞生长因子分泌显着较高，在10周后DEN，肝硬化阶段（LCP），比在3周后DEN，肝纤维化阶段（LFP）。相应地，在两个阶段之间注意到CD 8 + T细胞增殖和凋亡的差异。有趣的是，染色和TUNEL分析显示LFP组中的平滑肌肌动蛋白（α-SMA）+细胞凋亡（肝星状细胞（HSC）的标志物）低于LCP组，这表明HGF、CD 8 + T细胞和HSC之间在改善受损肝脏修复期间的纤维化负荷方面存在有益的相关性。在培养物中，当加入不同浓度的重组肝细胞生长因子（rHGF）时，植物血凝素（PHA）刺激的幼稚小鼠脾CD 8 + T细胞（pn-msCD 8 + T细胞）的反应不同;随着rHGF浓度的增加，pn-msCD 8 + T细胞克隆数减少，当rHGF浓度大于200 ng/mL时，克隆数显著减少。在400 ng/mL rHGF存在下，死亡诱导信号传导复合物（DISC）可在nsCD 8 + T细胞和健康人外周血CD 8 + T细胞（hp-CD 8 + T细胞）中直接活化，如FADD和半胱天冬酶-8的募集所示，因为DISC通过募集FADD和半胱天冬酶-8等形成。这些发现表明Fas介导的细胞凋亡也可能表明HGF信号在肝脏稳态中的调节作用。
Intrahepatic stem/progenitor cells and cytotoxic CD8+ T cells (CD8+ T cells) in the cirrhotic liver undergo apoptosis, which potentially facilitates progression to cancer. Here, we report that hepatocyte growth factor (HGF) signaling plays an important role in promoting normal and damaged liver CD8+ T cell Fas-mediated apoptosis through its only receptor, c-Met. In addition to binding with HGF, c-Met also binds to Fas to form a complex. Using a diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis mouse model, immunostaining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, we found that HGF secretion was significantly higher at 10 weeks post-DEN, the liver cirrhotic phase (LCP), than at 3 weeks post-DEN, the liver fibrotic phase (LFP). Correspondingly, differences in CD8+ T cell proliferation and apoptosis were noted between the two phases. Interestingly, staining and TUNEL assays revealed lower smooth muscle actin (α-SMA)+ cell apoptosis, a marker for hepatic stellate cells (HSCs), in the LFP group than in the LCP group, which suggested a beneficial correlation among HGF, CD8+ T cells and HSCs in improving the fibrotic load during damaged liver repair. In cultures, when met different concentrations of recombinant HGF (rHGF), phytohemagglutinin (PHA)-stimulated naive mouse splenic CD8+ T cells (pn-msCD8+ T cells) responded differently; as increases in rHGF increased were associated with decreases in the clonal numbers of pn-msCD8+ T cells, and when the rHGF dose was greater than 200 ng/mL, the clonal numbers significantly decreased. In the presence of 400 ng/mL rHGF, the death-inducing signaling complex (DISC) can be directly activated in both nsCD8+ T cells and healthy human peripheral blood CD8+ T cells (hp-CD8+ T cells), as indicated by recruitment of FADD and caspase-8 because DISC forms via the recruitment of FADD and caspase-8, among others. These findings suggest that Fas-mediated apoptosis, may also indicate a regulatory role of HGF signaling in hepatic homeostasis.
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转化生长因子β潜伏期：肝稳态和疾病中细胞因子储存和信号调节的机制。
DOI：
10.1016/j.jhepr.2021.100397
发表时间：
2022-03
期刊：
JHEP reports : innovation in hepatology
影响因子：
--
作者：
Li Y;Fan W;Link F;Wang S;Dooley S
通讯作者：
Dooley S
影响因子：
2.2
作者：
Huebner, Anastasia;Derkow, Katja;Braeuer, Anja U.
通讯作者：
Braeuer, Anja U.
影响因子：
16.6
作者：
Koda Y;Teratani T;Chu PS;Hagihara Y;Mikami Y;Harada Y;Tsujikawa H;Miyamoto K;Suzuki T;Taniki N;Sujino T;Sakamoto M;Kanai T;Nakamoto N
通讯作者：
Nakamoto N
影响因子：
25.7
作者：
Feldstein, AE;Canbay, A;Gores, GJ
通讯作者：
Gores, GJ
影响因子：
5.6
作者：
Chen, Quanyu;You, Yu;Bai, Lianhua
通讯作者：
Bai, Lianhua