Differential regulation of rodent hepatocyte and oval cell proliferation by interferon γ
Differential regulation of rodent hepatocyte and oval cell proliferation by interferon γ
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DOI：
10.1002/hep.20645
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发表时间：
2005-04-01
期刊：
影响因子：
13.5
通讯作者：
Fausto, N
中科院分区：
文献类型：
--
作者：
Brooling, JT;Campbell, JS;Fausto, N
肝细胞和肝内祖细胞（卵圆细胞）对大多数生长因子具有相似的反应，但很少一起增殖。卵圆细胞构成储备隔室，当肝细胞增殖被抑制时被激活。干扰素γ（IFN-γ）在涉及卵圆细胞反应的肝损伤中增加，但不上调。在部分肝切除术后的肝再生过程中。基于这些观察结果，我们使用了肝细胞（AML-12细胞）和卵圆细胞（LE-6细胞）的良好表征的细胞系来研究调节肝细胞和卵圆细胞中差异生长反应的潜在机制。我们表明，IFN-γ块肝细胞增殖在体内，并与肿瘤坏死因子（TNF）或脂多糖（LPS）相结合，它会导致细胞周期停滞在肝细胞，但刺激卵圆细胞增殖培养细胞。肝细胞周期阻滞是可逆的，是p53非依赖性的，并且与细胞凋亡无关。用IFN-γ/LPS或IFN-γ/TNF治疗AML-12肝细胞，但不与单个细胞因子，诱导NO合酶和产生NO，而类似的处理的卵圆细胞产生很少，如果任何NO。NO供体产生的NO再现了细胞因子组合对AML-12细胞复制的抑制作用，而NO抑制剂消除了复制缺陷。总之，我们提出，IFN-γ，与TNF或LPS，可以抑制肝细胞增殖，通过产生NO和刺激卵圆细胞复制。肝细胞和卵圆细胞对细胞因子组合的反应可能有助于这些细胞在肝生长过程中的差异增殖。
Hepatocytes and intrahepatic progenitor cells (oval cells) have similar responses to most growth factors but rarely proliferate together. Oval cells constitute a reserve compartment that is activated when hepatocyte proliferation is inhibited. Interferon gamma (IFN-gamma) increases in liver injury that involves oval cell responses, but it is not upregulated. during liver regeneration after partial hepatectomy. Based on these observations, we used well-characterized lines of hepatocytes (AML-12 cells) and oval cells (LE-6 cells) to investigate the potential mechanisms that regulate differential growth responses in hepatocytes and oval cells. We show that IFN-gamma blocks hepatocyte proliferation in vivo, and that in combination with either tumor necrosis factor (TNF) or lipopolysaccharide (LPS), it causes cell cycle arrest in hepatocytes; but stimulates oval cell proliferation in cultured cells. The hepatocyte cell cycle arrest is reversible, is p53-independent, and is not associated with apoptosis. Treatment of AML-12 hepatocytes with IFN-gamma/LPS or IFN-gamma/TNF, but not with individual cytokines, induced NO synthase and generated NO, while similarly treated oval cells produced little if any NO. Generation of NO by an NO donor reproduced the inhibitory effect of the cytokine combinations on AML-12 cell replication, while NO inhibitors abolish the replication deficiency. In conclusion, we propose that IFN-gamma, in conjunction with TNF or LPS, can both inhibit hepatocyte proliferation through the generation of NO and stimulate oval cell replication. The response of hepatocytes and oval cells to cytokine combinations may contribute to the differential proliferation of these cells in hepatic growth processes.