Interferon-gamma acts proapoptotic on Hepatic Stellate Cells (HSC) and abrogates the antiapoptotic Effect of Interferon-alpha by an HSP70 dependant Pathway

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 by 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 elicted 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, p21^WAF1, 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-HSP70M 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.

Key words

HSP70 - apoptosis - hepatic stellate cells