Major role of the soluble interleukin‐6/interleukin‐6 receptor complex for the proliferation of interleukin‐6‐dependent human myeloma cell lines

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Abstract
Interleukin‐6 (IL‐6) is a proinflammatory cytokine which possesses a central growth factor activity for certain tumor cells such as plasma cells in multiple myeloma (MM). Upon binding of IL‐6, soluble IL‐6 receptor (sIL‐6R) has been shown to retain its affinity for IL‐6 and to associate with the signal‐transducing gp130 chain. Therefore, contrary to the majority of soluble cytokine receptors, it plays an agonist role in IL‐6 signaling. In order to test its physiological importance as compared to that of its membrane counterpart, we studied cells from two myeloma cell lines which need exogenous IL‐6 to proliferate and release sIL‐6R into their culture supernatant. Using a new culture system where the supernatant recirculated permanently through an anti‐IL‐6R affinity column, all sIL‐6R was removed from the culture medium throughout the culture period. Under these conditions IL‐6‐dependent cells were unable to grow in the presence of physiological concentrations of IL‐6, showing the major role of the sIL‐6R for sustaining the proliferation of these cell lines. Increasing IL‐6 concentrations well over the physiological values allowed the cells to proliferate again. No effect was seen when sIL‐6R was removed from the supernatant of an IL‐6‐independent myeloma cell line. These results show that the levels of circulating sIL‐6R (and thus those of IL‐6/sIL‐6R complex) are worth looking at in pathologies involving IL‐6 hyperactivity.