Disruption by interferon-α 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 α- and β-chains

Abstract

IL-6 is an autocrine growth factor for U266 myeloma cells and their growth is inhibited by IFN-α or IL-6 mAb. We asked, therefore, whether IFN-α-induced growth inhibition involved IL-6. IFN-α and mAb against IL-6, the IL-6R α-(gp80) or β-chain (gp130) potently inhibited U266 cells. Remarkably, this effect occurred despite IFN-α-augmented secretion of endogenous IL-6. However, examining the IL-6R revealed that IFN-α drastically curtailed expression of the IL-6R α- and β-chain. This effect occurred on two different levels (protein and mRNA) and by two different mechanisms (directly and indirectly through IL-6). First, IFN-α, but not IL-6, greatly decreased gp80 and, to lesser extent, gp130 mRNA levels which resulted in a loss of IL-6 binding sites. Second, IFN-α-induced IL-6 predominantly down-regulated membrane-bound gp130. IFN-α-mediated decrease of gp80 levels was not detected on IL-6-independent myeloma (RPMI 8226) or myeloid cells (U937). We conclude that IFN-α inhibited IL-6-dependent myeloma cell growth by depriving U266 cells of an essential component of their autocrine growth loop, a functional IL-6R.