DIFFERENTIAL REGULATION OF INTERLEUKIN-6 RECEPTORS BY INTERLEUKIN-6 AND INTERFERONS IN MULTIPLE-MYELOMA CELL-LINES

Interleukin-6 (IL-6) mediates pleiotropic functions through specific r eceptors (IL-6R) composed of an 80-kDa binding protein, associated wit h a non-ligand binding protein (gp130) which transduces the signal. Be cause IL-6 is the major tumor growth factor in multiple myeloma,we inv estigated the regulation of IL-6R in two human multiple myeloma cell l ines. Binding experiments with I-125-labeled IL-6 showed that IL-6R we re expressed at a high density on RPMI-8226 cells (15 000 receptors/ce ll), but no specific binding was detected on XG-1 cells, whose growth depends on the presence of exogenous IL-6. However, when IL-6 was remo ved from the culture medium, high-affinity IL-6R appeared on the surfa ce of XG-1 cells (5300 sites/cell). Treatment of RPMI-8226 cells with IL-6 reduced the number of IL-6R without changing their affinity. This reduction was dose dependent and was not affected by acid treatment w hich dissociates ligand receptor complexes. Cross-linking experiments showed that the formation of one IL-6/receptor complex of 160 kDa mark edly decreased upon IL-6 treatment, while the other complex of 190 kDa became undetectable. These data provide evidence for ligand-induced d own-regulation of membrane IL-6R expression in myeloma cells. Treatmen t of RPMT-8226 cells with interferon-alpha (IFN-alpha), which inhibits the growth of these cells, stimulated IL-6R expression and increased the formation of the 160-kDa IL-6/receptor complex. This stimulation w as specific for IFN-alpha, since IFN-gamma reduced the number of IT-6R . These data indicate that, in myeloma cells, IL-6R are differentially regulated by IL-6 and IFN-alpha.