The hepatic stellate cell (HSC), the pericyte of the liver sinusoids belongs to the mesenchymal cells of the liver. Damaging noxae induce a transformation from the quiescent (vitamin A-storing cell) to the activated (connective tissue-producing cell) state. The balance between proapoptotic and surviving factors decides about the fate of the activated HSC. Interferon-alpha (IFN-alpha) has been shown to elicit antiproliferative and/or antifibrogenic effects in various cell types of mesenchymal origin. We therefore investigated the effect of IFN-alpha on primary cultured rat HSC in their quiescent (day 2) and activated state (day 7). IFN-alpha significantly inhibited spontaneous apoptosis in activated HSC in vitro and simultaneously inhibited cell cycle progression by inducing a G1 arrest. The effect of IFN-a is not accompanied by a modulation of CD95, CD95L, p53, p21(WAF1), p27, bcl-2, bcl-xL, bax, NFkappaB, or IkappaB gene expression. Surprisingly, the IFN-alpha effect could be abolished completely by blocking JAK2 activity or JAK2 translation. The downregulating effect of IFN-alpha on the activity of caspase-8 and caspase-3 could also be neutralized using tyrphostin AG490 or JAK-2 antisense. Taken together IFN-alpha inhibits apoptosis of activated HSC by activation of JAK2 which inhibits the caspase-8 apoptosis pathway.

中文翻译：

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干扰素-α对肝星状细胞（HSC）的抗凋亡作用：通过Janus激酶2（JAK2）和caspase-8进行IFN-α信号转导的新途径。

肝星状细胞的肝周细胞是肝星状细胞（HSC），它属于肝脏的间质细胞。破坏性的诺克斯藻会诱导从静止（维他命A储存细胞）到活化（结缔组织产生细胞）状态的转化。凋亡因子和存活因子之间的平衡决定了活化HSC的命运。干扰素-α（IFN-α）已显示在间充质来源的各种细胞类型中引起抗增殖和/或抗纤维化作用。因此，我们研究了IFN-α对处于静止状态（第2天）和激活状态（第7天）的原代培养的大鼠HSC的影响。IFN-α在体外可明显抑制激活的HSC中的自发凋亡，并通过诱导G1阻滞同时抑制细胞周期进程。IFN-α的作用不会伴随CD95，CD95L，p53，p21（WAF1），p27，bcl-2，bcl-xL，bax，NFkappaB或IkappaB基因表达的调节。令人惊讶的是，通过阻断JAK2活性或JAK2翻译，可以完全消除IFN-α的作用。IFN-α对caspase-8和caspase-3活性的下调作用也可以使用酪蛋白原AG490或JAK-2反义中和。总之，IFN-α通过激活JAK2抑制激活的HSC的凋亡，而JAK2抑制caspase-8凋亡途径。IFN-α对caspase-8和caspase-3活性的下调作用也可以使用酪蛋白原AG490或JAK-2反义中和。总之，IFN-α通过激活JAK2来抑制激活的HSC的凋亡，而JAK2抑制了caspase-8凋亡途径。IFN-α对caspase-8和caspase-3活性的下调作用也可以使用酪蛋白原AG490或JAK-2反义中和。总之，IFN-α通过激活JAK2来抑制激活的HSC的凋亡，而JAK2抑制了caspase-8凋亡途径。