Constituents of autocrine IL-6 loops in myeloma cell lines and their targeting for suppression of neoplastic growth by antibody strategies

Abstract

We examined the constitution and biological relevance of an autocrine IL‐6/IL‐6‐receptor (r) loop in 7 multiple myeloma and plasma‐cell leukemia lines in order to determine its biological role and potential therapeutic impact on antibody strategies. The expression and constitution of the IL‐6r [i.e. membrane‐bound gp‐80, soluble (s)gp‐55 and the gp‐130 IL‐6 signal‐transducing element (str)], the binding capacity of the membrane‐associated receptor(s) for IL‐6, the production and secretion of IL‐6 by neoplastic plasma cells, and the effect of IL‐6 on tumor‐cell proliferation were investigated. In the U‐266 cell line, the growth‐inhibitory effects of antibodies (Abs) against IL‐6 and the IL‐6‐binding subunit of its receptor were compared with each other. From our results the following conclusions may be drawn: (i) Substantial differences in the quantificative assembly of the IL‐6r constituents and in the response to recombinant (r) human (h) IL‐6 became evident in the 7 myeloma cell lines. (ii) The components of an autocrine IL‐6 loop may be regulated in an independent and, in the case of IL‐6 and sgp‐55, probably counteractive manner. (iii) The level of endogenous IL‐6 and the reservoir of recruitable sgp‐55 were important for the response to exogenous rhIL‐6. (iv) Apart from IL‐6, other growth factors are important for the propagation of myeloma cells but at least some of them exert their effect through an IL‐6‐dependent pathway. Their growth‐promoting activity, as well as that of IL‐6, may be successfully targeted by immunological means, with Abs against the IL‐6r being more efficient than those against the ligand.