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Interleukin-6-Induced Inhibition of Multiple Myeloma Cell
Apoptosis: Support for the Hypothesis That Protection Is
Mediated Via Inhibition of the JNK/SAPK Pathway
Feng-hao Xu,
Sanjesh Sharma,
Agnes Gardner,
Yiping Tu,
Arthur Raitano,
Charles Sawyers, and
Alan Lichtenstein
From the Department of Medicine, West LA VA Medical Center, and
Jonsson Comprehensive Cancer Center, Los Angeles; and the Department of
Medicine, UCLA Medical Center, Los Angeles, CA.
The mechanism by which interleukin-6 (IL-6) protects multiple
myeloma (MM) plasma cells from apoptosis induced by
anti-fas antibodies and dexamethasone was studied.
Anti-apoptotic concentrations of IL-6 had no effect on cell-cycle
distribution or activation of RAF-1 or ERK in dexamethasone- or
anti-fas-treated 8226 and UCLA #1 MM cell lines. However,
IL-6-dependent protection of viability correlated with an inhibition
of dexamethasone- and anti-fas-induced activation of
jun kinase (JNK) and AP-1 transactivation. To test the
hypothesis that cytokine-induced protection was mediated through inhibition of JNK/c-jun, we also inhibited c-jun
function in 8226 cells via introduction of a mutant dominant negative
c-jun construct. Mutant c-jun-containing MM cells were
also resistant to anti-fas-induced apoptosis but were
significantly more sensitive to dexamethasone-induced apoptosis. These
results support the notion that IL-6 protects MM cells against
anti-fas through its inhibitory effects on JNK/c-jun but indicate protection against dexamethasone occurs through separate, yet unknown pathways.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 241-251
© 1998 by The American Society of Hematology.
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