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Is a Survival Factor for Human Myeloma Cells and Reduces Dexamethasone-Induced Apoptosis1
*
Institut National de la Santé et de la Recherche Médicale, Unit 475,
Service des Maladies du Sang B, Centre Hospitalier Universitaire Montpellier, and
Unit for Cellular Therapy, Centre Hospitalier Universitaire Montpellier, Hôpital Saint Eloi, Montpellier, France
IFN-
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- can both stimulate and inhibit myeloma cell
proliferation. We have tested the effect of IFN- on the survival of
myeloma cell lines and primary plasma cells. IFN- 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- promoted the survival of
myeloma cells, which, following removal of IL-6, were blocked in G1 and
died. However, unlike IL-6, IFN--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--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- or IL-6 resulted in STAT3
phosphorylation. These results indicate that IFN- 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- on myeloma cell
proliferation.
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