Differential human multiple myeloma cell line responsiveness to interferon-α: Analysis of transcription factor activation and interleukin 6 receptor expression

Abstract

Although IFN-α is commonly used as maintenance treatment for multiple myeloma patients, its effectiveness is varied. In this study, we have used a panel of IL-6 responsive myeloma cell lines that vary remarkably in responsiveness to IFN-α. Three cell lines were growth arrested by IFN-α; however, IFN-α significantly stimulated growth of the fourth cell line, KAS- 6/1. Our studies have focused on elucidating the mechanism of differential IFN-α responsiveness. First, we have shown that IFN-α-stimulated growth of the KAS-6/1 cells did not result from induction of autocrine IL-6 expression. Second, analysis of Stats 1; 2, and 3 and IFN regulatory factor-1 (IRF-1) and IRF-2 activation failed to reveal differences between the IFN-α growth- arrested or growth-stimulated cells. Third, although IFN-α treatment of the IFN-α growth-inhibited cell lines reduced IL-6 receptor (IL-6R) expression, IFN-α also reduced KAS-6/1 IL-6R expression. Finally, although IFN-α treatment reduced IL-6R numbers on each cell line, analysis of Stat protein activation revealed that the receptors were still functional. We conclude that myeloma cell responsiveness to IFN-α is heterogeneous and that mechanisms of IFN-α-mediated growth inhibition other than IL-6R downregulation must exist in myeloma. Identification of these mechanisms may allow development of agents that are more universally effective than IFN-α.