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Primary tumor cells of myeloma patients induce interleukin-6 secretion in
long-term bone marrow cultures
HM Lokhorst, T Lamme, M de Smet, S Klein, RA de Weger, R van Oers and AC Bloem
Department of Hematology, University Hospital Utrecht, The Netherlands.
Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma
(MM) and normal donors were analyzed for immunophenotype and cytokine
production. Both LTBMC adherent cells from myeloma and normal donor origin
expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell
adhesion molecule 1, very late antigen 2 (VLA-2), and VLA- 5, and were
positive for extracellular matrix components fibronectin, laminin, and
collagen types 3 and 4. LTBMC from myeloma patients and normal donors
spontaneously secreted interleukin-6 (IL-6). However, levels of IL-6
correlated with the stage of disease; highest levels of IL-6 were found in
LTBMC from patients with active myeloma. To identify the origin of IL-6
production, LTBMC from MM patients and normal donors were cocultured with
BM-derived myeloma cells and cells from myeloma cell lines. IL-6 was
induced by plasma cell lines that adhered to LTBMC such as ARH-77 and
RPMI-8226, but not by nonadhering cell lines U266 and FRAVEL. Myeloma cells
strongly stimulated IL-6 secretion in cocultures with LTBMC adherent cells
from normal donors and myeloma patients. When direct cellular contact
between LTBMC and plasma cells was prevented by tissue-culture inserts, no
IL-6 production was induced. This implies that intimate cell-cell contact
is a prerequisite for IL-6 induction. Binding of purified myeloma cells to
LTBMC adherent cells was partly inhibited by monoclonal antibodies against
adhesion molecules VLA-4, CD44, and lymphocyte function-associated antigen
1 (LFA-1) present on the plasma cell. Antibodies against VLA-4, CD29, and
LFA-1 also inhibited the induced IL-6 secretion in plasma cell-LTBMC
cocultures. In situ hybridization studies performed before and after
coculture with plasma cells indicated that LTBMC adherent cells produce the
IL-6. These results suggest that the high levels of IL-6 found in LTBMC of
MM patients with active disease are a reflection of their previous contact
with tumor cells in vivo. These results provide a new perspective on tumor
growth in MM and emphasize the importance of plasma cell-LTBMC interaction
in the pathophysiology of MM.
Volume 84,
Issue 7,
pp. 2269-2277,
10/01/1994
Copyright © 1994 by The American Society of Hematology
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