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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 610-618
Expression of functional interleukin-15 receptor and autocrine
production of interleukin-15 as mechanisms of tumor propagation in
multiple myeloma
Inge Tinhofer,
Ingrid Marschitz,
Traudl Henn,
Alexander Egle, and
Richard Greil
From the Laboratory of Molecular Cytology, Department of Internal
Medicine, University of Innsbruck, Innsbruck, Austria.
Interleukin-15 (IL-15) induces proliferation and promotes cell
survival of human T and B lymphocytes, natural killer cells, and
neutrophils. Here we report the constitutive expression of a functional
IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in
CD38high/CD45low plasma cells belonging to 14 of 14 patients with multiple myeloma. Furthermore, we detected IL-15
transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell
lines and also in the primary plasma cells of 8/14 multiple myeloma
patients. Our observations confirm the existence of an autocrine IL-15
loop and point to the potential paracrine stimulation of myeloma cells
by IL-15 released from the cellular microenvironment. Blocking
autocrine IL-15 in cell lines increased the rate of spontaneous
apoptosis, and the degree of this effect was comparable to the
pro-apoptotic effect of depleting autocrine IL-6 by antibody targeting.
IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa. In short-term cultures of primary
myeloma cells, the addition of IL-15 reduced the percentage of tumor
cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered
the responsiveness to Fas-induced apoptosis and to cytotoxic treatment
with vincristine and doxorubicin but not with dexamethasone. These data
add IL-15 to the list of important factors promoting survival of
multiple myeloma cells and demonstrate that it can be produced and be
functionally active in an autocrine manner.
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