Antiapoptotic effect of interferon-α on hepatic stellate cells (HSC): A novel pathway of IFN-α signal transduction via Janus kinase 2 (JAK 2) and caspase-8

Abstract

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-α (IFN-α) has been shown to elicit antiproliferative and/or antifibrogenic effects in various cell types of mesenchymal origin. We therefore investigated the effect of IFN-α on primary cultured rat HSC in their quiescent (day 2) and activated state (day 7). IFN-α significantly inhibited spontaneous apoptosis in activated HSC in vitro and simultaneously inhibited cell cycle progression by inducing a G1 arrest. The effect of IFN-α is not accompanied by a modulation of CD95, CD95L, p53, p21WAF1, p27, bcl-2, bcl-XL, bax, NFκB, or IκB gene expression. Surprisingly, the IFN-α effect could be abolished completely by blocking JAK2 activity or JAK2 translation. The downregulating effect of IFN-α on the activity of caspase-8 and caspase-3 could also be neutralized using tyrphostin AG490 or JAK-2 antisense. Taken together IFN-α inhibits apoptosis of activated HSC by activation, of JAK2 which inhibits the caspase-8 apoptosis pathway.