Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor.
Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor.
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发表时间：
1998-06
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通讯作者：
Yasuhiro Yamada;N. Fausto
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作者：
Yasuhiro Yamada;N. Fausto
肿瘤坏死因子1型受体(TNFR-1)是肝部分切除后启动肝再生所必需的信号通路。利用缺乏TNFR-1或TNFR-2的基因敲除小鼠，我们确定了通过肿瘤坏死因子受体传递的信号是否在四氯化碳(CCl4)诱导的肝损伤和肝细胞增殖中起重要作用。CCl_4注射后缺乏TNFR-1抑制肝细胞DNA合成。在注射后44小时，根据注射剂量的不同，TNFR-1中肝细胞的复制比野生型(WT)动物低50%到90%。在WT动物中，肝细胞复制在注射CCl4后4天基本完成，但在TNFR-1小鼠中，低水平复制至少持续了2周。在CCl4后的前5小时内，TNFR-1基因敲除小鼠几乎没有检测到核因子-kappa B和STAT3的结合，血浆中高水平的肿瘤坏死因子，以及血浆中IL-6和肝脏中IL-6的mRNA水平降低。CCl_4注射前30分钟注射IL-6可纠正44小时肝细胞复制缺陷，并使STAT3结合恢复到正常水平。相反，缺乏TNFR-2的小鼠在核因子-kappa B和STAT3结合、IL-6和肿瘤坏死因子水平以及肝细胞复制方面与WT小鼠没有显著差异。虽然在WTTNFR-1和TNFR-2基因敲除小鼠中可诱导AP-1结合，但在TNFR-2基因敲除小鼠中的结合低于WT小鼠。TNFR-1和TNFR-2基因敲除小鼠的c/EBP结合率明显低于WT小鼠。根据形态分析和丙氨酸氨基转移酶水平的评估，CCl4造成的急性损伤在三组动物中似乎是相似的，但缺乏TNFR-1的小鼠随后的再生受到损害。我们的结论是，包括核因子-kappaB、IL-6和STAT3在内的TNFR-1信号通路是CCl4损伤诱导的小鼠肝细胞有丝分裂反应的重要组成部分。
Signaling by tumor necrosis factor type 1 receptor (TNFR-1) is required for the initiation of liver regeneration after partial hepatectomy. Using knockout mice that lack either TNFR-1 or TNFR-2, we determined whether signaling through TNF receptors is important for liver injury and hepatocyte proliferation induced by carbon tetrachloride (CCl4). Lack of TNFR-1 inhibited hepatocyte DNA synthesis after CCl4 injection. At 44 hours after the injection, replication of hepatocytes in TNFR-1 was 50% to 90% lower than in wild-type (WT) animals, depending on the dose injected. In WT animals, hepatocyte replication was essentially completed by 4 days after CCl4 injection, but replication at a low level persisted in TNFR-1 mice for at least 2 weeks. TNFR-1 knockout mice had little detectable NF-kappa B and STAT3 binding during the first 5 hours after CCl4, high plasma TNF, and reduced levels of plasma interleukin (IL)-6 and liver IL-6 mRNA. Injection of IL-6 30 minutes before CCl4 administration corrected the deficiency of hepatocyte replication at 44 hours and restored STAT3 binding to normal levels. In contrast, mice lacking TNFR-2 did not differ significantly from WT mice in NF-kappa B and STAT3 binding, IL-6 and TNF levels, or hepatocyte replication. Although AP-1 binding was induced in WT TNFR-1 and TNFR-2 knockout mice, binding in TNFR-2 knockouts was lower than in WT mice. C/EBP binding was much lower in TNFR-1 and TNFR-2 knockout mice than in WT mice. As assessed by morphological analysis and alanine aminotransferase levels, the acute injury caused by CCl4 appeared to be similar in the three groups of animals, but subsequent regeneration was impaired in mice lacking TNFR-1. We conclude that a TNFR-1 signaling pathway involving NF-kappa B, IL-6, and STAT3 is an important component of the hepatocyte mitogenic response induced by CCl4 injury in mouse liver.