Interleukin 6 receptor superantagonists are potent inducers of human multiple myeloma cell death.
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 alpha 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 alpha, 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.
Demartis
A
A
Istituto di Ricerche di Biologia Molecolare, P. Angeletti, Pomezia, Rome.
Bernassola
F
F
Savino
R
R
Melino
G
G
Ciliberto
G
G
D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins