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CD40 ligand triggered interleukin-6 secretion in multiple myeloma
M Urashima, D Chauhan, H Uchiyama, GJ Freeman and KC Anderson
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston,
MA 02115, USA.
Previous studies have suggested that interleukin-6 (IL-6) may mediate
growth of multiple myeloma (MM) in either an autocrine or paracrine growth
mechanism. However, those molecules which can trigger IL-6 secretion either
by tumor cells or non-MM marrow cells are not well characterized. In the
present study, we have examined the expression and functional significance
of CD40 on MM and plasma cell leukemia (PCL) cells and derived cell lines,
as well as long-term bone marrow stromal cells (BMSCs) and derived cell
lines. CD40 was expressed on the majority of MM cells (> 90%) and BMSCs
(> 70%). Triggering via CD40 using NIH3T3 CD40 ligand transfectant
(CD40LT) cells increased (> 30%) cell surface CD80, CD18, CD11a, CD11b,
and CD11c expression on MM cell lines. Culture with either fresh or
paraformaldehyde fixed NIH3T3 CD40LT cells upregulates IL-6 secretion in MM
cells and MM-derived cell lines, as well as normal and MM bone marrow
mononuclear cells (BMMCs), BMSCs, and BMSC lines; this effect can be
specifically blocked by anti- CD40 monoclonal antibody (MoAb). BMMCs and
BMSCs from patients with MM secreted significantly more IL-6 than those
from healthy donors (n = 3, P < .001); moreover, after stimulation using
CD40L, IL-6 secretion was fourfold greater (n = 3, P < .001) from MM
BMMCs and BMSCs than from normal BMMCs and BMSCs. Myeloma (CD38+CD45RA-)
cells and non-MM (CD38+CD45RA+, CD38-CD45RA+, and CD38-CD45RA-) BMMCs were
separated by dual fluorescence cell sorting. The latter secreted fourfold
more IL-6 than the former (n = 2, P < .001). Increased IL-6 secretion
(up to 28- fold) and proliferation (Stimulation index 10) by CD38+CD45RA-MM
cells was triggered by culture with NIH3T3 CD40LT cells. Finally, anti-
CD40MoAb partially (30%) blocked tumor cell to BMSC adhesion-induced IL- 6
secretion. These studies support the view that CD40L may trigger IL-6
secretion by both MM cells and BMSCs and that IL-6-mediated autocrine and
paracrine growth mechanisms may be possible in MM.
Volume 85,
Issue 7,
pp. 1903-1912,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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