DISRUPTION BY INTERFERON-ALPHA OF AN AUTOCRINE INTERLEUKIN-6 GROWTH LOOP IN IL-6-DEPENDENT U266 MYELOMA CELLS BY HOMOLOGOUS AND HETEROLOGOUS DOWN-REGULATION OF THE IL-6 RECEPTOR ALPHA-CHAIN AND BETA-CHAIN

IL-6 is an autocrine growth factor for U266 myeloma cells and their gr owth is inhibited by IFN-alpha or IL-6 mAb. We asked, therefore, wheth er IFN-alpha-induced growth inhibition involved IL-6. IFN-alpha and mA b against IL-6, the IL-6R alpha-(gp80) or beta-chain (gp130) potently inhibited U266 cells. Remarkably, this effect occurred despite IFN-alp ha-augmented secretion of endogenous IL-6. However, examining the IL-6 R revealed that IFN-alpha drastically curtailed expression of the IL-6 R alpha- and beta-chain. This effect occurred on two different levels (protein and mRNA) and by two different mechanisms (directly and indir ectly through IL-6). First, IFN-alpha, but not IL-6, greatly decreased gp80 and, to a lesser extent, gp130 mRNA levels which resulted in a l oss of IL-6 binding sites. Second, IFN-alpha-induced IL-6 predominantl y downregulated membrane-bound gp130. IFN-alpha-mediated decrease of g p80 levels was not detected on IL-6-independent myeloma (RPMI 8226) or myeloid cells (U937). We conclude that IFN-alpha inhibited IL-6-depen dent myeloma cell growth by depriving U266 cells of an essential compo nent of their autocrine growth loop, a functional IL-6R.