Dissociation Between IFN-α-Induced Anti-Viral and Growth Signaling Pathways

Abstract

The ability of IFN-α to induce an anti-viral state in a wide variety of cell types as well as to inhibit cellular growth has long been appreciated. It is less clear, however, whether both these effects lie downstream of a common signaling pathway. In this study we have taken advantage of an atypical human myeloma cell line (KAS-6/1) displaying a dramatic proliferative response to IFN-α in an effort to resolve the signaling requirements for IFN-α-induced anti-viral and growth regulatory effects. Thus, we have analyzed the ability of IFN-α to induce a number of known receptor-initiated events in this cell line and have compared these responses with those exhibited by a cell lineage- and maturation stage-matched myeloma cell line (ANBL-6) that displays typical IFN-α responsiveness. Despite the widely contrasting effects of IFN-α on cellular proliferation, IFN-α was shown to be comparable in its ability to induce the expression of early response genes as well as induce resistance to viral infection in both cell lines. By contrast, the effects of IFN-α on the activation of mitogen-activated protein kinase (MAPK) were strikingly distinct. Finally, although inhibition of MEK and MAPK activation had no effect on the induction of the anti-viral response, it completely blocked IFN-α-stimulated proliferation of the KAS-6/1 cells. In summary, our analysis of the role of the MAPK and anti-viral signaling pathways using these two cell lines suggests that the anti-viral and growth regulatory effects of IFN-α display a differential requirement for activation of the MAPK pathway.