Constituents of autocrine IL-6 loops in myeloma cell lines and their targeting for suppression of neoplastic growth by antibody strategies.
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 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.
Villunger
A
A
Department of Internal Medicine, University of Innsbruck, Austria.
Egle
A
A
Kos
M
M
Hittmair
A
A
Maly
K
K
Greil
R
R
D000906:Antibodies / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6