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Istituto di Ricerche di Biologia Molecolare, P. Angeletti, Via Pontina, km 30,600, 00040 Pomezia, Rome [A. D., R. S., G. C.]; Istituto Dermapatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Biochemistry Lab, 00167 Rome [F. B., G. M.]; University of L'Aquila, 67100 L'Aquila [G. M.], Italy
Interleukin-6 (IL-6) plays a central role in the pathogenesis of multiple myeloma, acting as both a growth and a survival factor for myeloma cells. A series of IL-6 receptor antagonists that are IL-6 variants has been recently obtained, the affinity of which for the ligand-specific receptor chain IL-6R
has been maintained or even increased, but the signaling of which is impaired by not being able to bind and/or dimerize the signaling chain gp130. Although IL-6 antagonists have been shown to inhibit the growth of IL-6-dependent myeloma, no information has been gathered on their ability to induce myeloma cell death. We show here that IL-6 receptor antagonists are pro-apoptotic factors for the IL-6-dependent human myeloma cell line XG-1. Their capacity to induce cell death is in direct relation to their affinity for IL-6R, degree of gp130 binding impairment, and efficiency to inhibit intracellular signaling events. Interestingly, the most potent pro-apoptotic molecule, Sant7, counteracts the protective autocrine effect exercised by the limited amounts of IL-6 produced by XG-1 cells and is thus able to induce cell death at higher rate than just IL-6 deprivation. These findings are particularly relevant for the therapy of multiple myeloma.
1 To whom requests for reprints should be addressed.
Received 4/ 1/96. Accepted 7/16/96.
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