PROTECTIVE EFFECT OF HEPATOCYTE GROWTH-FACTOR ON INTERFERON-GAMMA-INDUCED CYTOTOXICITY IN MOUSE HEPATOCYTES
PROTECTIVE EFFECT OF HEPATOCYTE GROWTH-FACTOR ON INTERFERON-GAMMA-INDUCED CYTOTOXICITY IN MOUSE HEPATOCYTES
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DOI：
10.1016/0270-9139(95)90463-8
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发表时间：
1995-06-01
期刊：
影响因子：
13.5
通讯作者：
AKAIKE, T
中科院分区：
文献类型：
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作者：
MORITA, M;WATANABE, Y;AKAIKE, T
我们检查了可能与肝炎有关的几种细胞因子（白细胞介素-1β[IL-1β]、肿瘤坏死因子α[TNF-α]、干扰素γ[INF-γ]、IL-6、IFN-α/β和肝细胞生长因子[HGF]）对原代培养的小鼠肝细胞的相互作用。在这些细胞因子中，只有IFN-γ以时间和剂量依赖性方式诱导肝细胞释放LDH。含抗血清的抗小鼠IFN-γ单克隆抗体(R4-6A2)可抑制细胞毒性作用。此外，有趣的是，根据基因组 DNA 凝胶电泳和流式细胞术分析，IFN-γ 以时间和剂量依赖性方式诱导肝细胞中的 DNA 断裂。这些结果表明IFN-γ对肝细胞的细胞毒作用是由诱导性细胞凋亡引起的。 HGF 以剂量依赖性方式抑制 IFN-γ 诱导的 LDH 释放和 DNA 断裂，而 TNF-α 似乎加速了这些过程。对处理过的肝细胞的细胞核进行流式细胞术分析证实了 DNA 降解中的相互作用。培养的肝细胞的DNA合成也被IFN-γ减少，但被肝细胞生长因子恢复。综上所述，IFN-γ被认为是肝损伤中关键的细胞因子，IFN-γ、TNF-α和HGF组成的网络可能在肝损伤的调节中发挥重要作用。
We examined the interactive effect of several cytokines (interleukin-1 beta [IL-1 beta], tumor necrosis factor alpha [TNF-alpha], interferon gamma [INF-gamma], IL-6, IFN-alpha/beta, and hepatocyte growth factor [HGF]) presumably involved in hepatitis, on primary cultured murine hepatocytes. Among these cytokines, only IFN-gamma induced LDH release from hepatocytes in both time- and dose-dependent fashions, The cytotoxic effect was inhibited by antiserum-containing anti-mouse IFN-gamma monoclonal antibodies (R4-6A2). Moreover, intriguingly, IFN-gamma induced DNA fragmentation in the hepatocytes in a time- and dose-dependent fashion according to the gel electrophoresis of genomic DNA and flow cytometry analysis. These results suggest that the cytotoxic effect of IFN-gamma on hepatocytes was caused by inductive apoptosis. The LDH release and DNA fragmentation induced by IFN-gamma were inhibited by HGF in a dose-dependent manner, whereas they seemed to be accelerated by TNF-alpha. Flow cytometry analysis of the nuclei of treated hepatocytes confirmed the interactions in DNA degradation. The DNA synthesis of cultured hepatocytes was also reduced by IFN-gamma but recovered by hepatocyte growth factor. Taken together, IFN-gamma is presumed to be a critical cytokine in hepatic damage, and the network composed of IFN-gamma, TNF-alpha, and HGF may play an important role in the regulation of liver injury.