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/IL6-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 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 rhlL-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.