IFN-alpha is a survival factor for human myeloma cells and reduces dexamethasone-induced apoptosis.
IFN-alpha is used as a maintenance therapy in patients with multiple myeloma, but its benefit is a matter of controversy. In vitro studies show that IFN-alpha can both stimulate and inhibit myeloma cell proliferation. We have tested the effect of IFN-alpha on the survival of myeloma cell lines and primary plasma cells. IFN-alpha significantly reduced the apoptosis induced by removal of IL-6 in four IL-6-dependent myeloma cell lines. It also reduced the level of apoptosis induced by dexamethasone in these cell lines as well as in purified primary myeloma cells from seven patients. IFN-alpha promoted the survival of myeloma cells, which, following removal of IL-6, were blocked in G1 and died. However, unlike IL-6, IFN-alpha-treated cells remained mainly blocked in the G1 phase of the cycle. While the effects of IL-6 are mediated through stimulation of its gp130 receptor subunit, the IFN-alpha-induced survival of myeloma cells was independent of gp130 transducer activation (as demonstrated using a neutralizing anti-gp130 Ab). However, the signal transduction cascades activated by these two cytokines share at least some common elements, since stimulation with either IFN-alpha or IL-6 resulted in STAT3 phosphorylation. These results indicate that IFN-alpha promotes the survival, but not the proliferation, of myeloma cells, preventing the apoptosis induced by removal of IL-6 or addition of dexamethasone. This survival factor activity may explain the conflicting reports on the effects of IFN-alpha on myeloma cell proliferation.
Ferlin-Bezombes
M
M
Institut National de la Santé et de la Recherche Médicale, Unit 475, Montpellier, France.
Jourdan
M
M
Liautard
J
J
Brochier
J
J
Rossi
J F
JF
Klein
B
B
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000502:physiology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D016207:Cytokines; C494199:IL6ST protein, human; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D050822:Cytokine Receptor gp130; D003907:Dexamethasone