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Blood, 15 January 2001, Vol. 97, No. 2, pp. 483-489
IMMUNOBIOLOGY
Autocrine interleukin-6 production and highly malignant multiple
myeloma: relation with resistance to drug-induced apoptosis
Maria Antonia Frassanito,
Antonio Cusmai,
Giuseppe Iodice, and
Franco Dammacco
From the Department of Biomedical Sciences and Human
Oncology, Section of Internal Medicine and Clinical Oncology,
University of Bari Medical School, Bari, Italy.
In this study, flow cytometry was used to evaluate interleukin-6
(IL-6) production by bone marrow mononuclear cells from 47 patients
with multiple myeloma (MM) in different clinical stages and 15 patients
with monoclonal gammopathy of undetermined significance. In patients
with MM, autocrine IL-6 production paralleled the clinical disease
stage. The largest proportion of
syndecan-1+/IL-6+ cells was detected in
patients with resistant relapse or primary refractory disease,
suggesting that tumor progression involves expansion of myeloma cells
producing IL-6. The authors assessed autocrine IL-6 production and in
vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell
clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970,
which showed different sensitivities to the addition of exogenous IL-6.
Autocrine IL-6 production was observed in IL-6-independent MCC-2,
MCC-3, and MCC-5 cloned from patients with aggressive disease and in
the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-6 were syndecan-1+ and IL-6 . Blocking
experiments with anti-IL-6 monoclonal antibody from clone AH65, which
binds IL-6-IL-6R complexes, prevented cell proliferation of
IL-6+ MCCs. Flow cytometry evaluations after propidium
iodide staining revealed different susceptibilities of MCCs to
cell death. IL-6-producing MCCs showed minimal spontaneous and
dexamethasone-induced apoptosis, whereas a regular amplitude of
apoptosis occurred in the IL-6 MCCs. These data provide
evidence that autocrine IL-6 reflects a highly malignant phenotype of
myeloma cells. In fact, autocrine IL-6 production and deregulated
apoptosis may induce expansion of selective IL-6+ myeloma
cells resistant to spontaneous and drug-induced cell death.
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