Interferon-α acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-α by an HSP70-dependant pathway

Abstract

The activated hepatic stellate cell (HSC) is an important fibrogenic cell type of the liver. Interferon-α (IFN-α) has recently been shown to elicit an antiapoptotic effect on activated HSC a JAK-2-dependent inhibition of caspase-8 activation. As JAK-2 has so far been shown to be a member of the IFN-γ signal transduction pathway we studied the effect of IFN-γ on apoptosis as well as on its signaling in primary cultured rat HSC. IFN-γ elicited a proapoptotic effect in activated HSC. The combination of both, IFN-γ and IFN-α, however, completely cancelled each other's effect. No effect of the two cytokines on major members of apoptosis-regulating systems (CD95, CD95L, bcl-2, bax, bcl-xL, p53, p21WAFI, p27, NFκB) could be observed. Western Blot analysis revealed that gene expression of the chaperone HSP70 was found to be downregulated by IFN-γ but upregulated by IFN-α. The effect could be abrogated by administration of both. After transfection of activated HSC with a pCMV-HSP70 M expression vector the proapoptotic effect of IFN-γ was cancelled. Using HSP70 antisense, the antiapoptotic effect of IFN-α was cancelled as well. However IFN-γ had no effect on upregulation of JAK-2 and pJAK-2 by IFN-α. Taken together IFN-γ and IFN-α exert opposite effects on apoptosis in HSC. This effect is mediated by their counteracting effect on HSP70 expression which acts antiapoptotic at the level of caspase-8.