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 receptors (IL-6R) composed of an 80-kDa binding protein, associated with a non-ligand binding protein (gp130) which transduces the signal. Because IL-6 is the major tumor growth factor in multiple myeloma, we investigated the regulation of IL-6R in two human multiple myeloma cell lines. Binding experiments with 125I-labeled IL-6 showed that IL-6R were expressed at a high density on RPMI-8226 cells (15 000 receptors/cell), 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 removed from the culture medium, high-affinity IL-6R appeared on the surface 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 which dissociates ligand-receptor complexes. Cross-linking experiments showed that the formation of one IL-6/receptor complex of 160 kDa markedly decreased upon IL-6 treatment, while the other complex of 190 kDa became undetectable. These data provide evidence for ligand-induced down-regulation of membrane IL-6R expression in myeloma cells. Treatment of RPMI-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 was specific for IFN-alpha, since IFN-gamma reduced the number of IL-6R. These data indicate that, in myeloma cells, IL-6R are differentially regulated by IL-6 and IFN-alpha.
Unité 365 INSERM Interférons et Cytokines Institut Curie, Paris, France.
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Lasfar
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Wietzerbin
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Billard
D001667:Binding, Competitive; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D009101:Multiple Myeloma / Q000276:immunology*; D011869:Radioligand Assay; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D019947:Receptors, Interleukin-6; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6