With the use of the CD40 monoclonal antibody (MoAb) G28-5, we examined CD40 expression and the effect of CD40 binding on MM clonogenic colony (MCC) formation to characterize the IL-6/CD40 loop activity in MM.
Surprisingly this antagonistic IL-6 variant had an agonistic effect on the human myeloma cell line XG-1, albeit at a 1000-fold higher concentration than wild type IL-6.
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.
Inhibition of PGE2 synthesis (as obtained with indomethacin and the IL-1RA) might be helpful to inhibit myeloma cell proliferation by reducing IL-1-induced endogenous IL-6 production not only in vitro (as demonstrated here) but also in vivo.
Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb.
Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture.
Our attempts to block MM cell adhesion to BMSC-induced IL-6 secretion by using antibodies to CD29/CDw49d, CD18/11a, and/or CD44 demonstrated minimal effects, suggesting that another ligand-receptor interaction triggers IL-6 secretion when MM cells and BMSCs are juxtaposed.Both MM cells and BMSCs express CD40.
Establishment of a novel myeloma cell line KPMM2 carrying t(3;14)(q21;q32), which proliferates specifically in response to interleukin-6 through an autocrine mechanism.
The cytokine IL-6 has been proposed as an autocrine growth factor in multiple myeloma, and is also required for stimulation of immunoglobulin production and secretion in normal plasma cells and myeloma cells.
Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6.
It might therefore be possible to develop innovative treatment strategies either to inhibit interleukin 6 production or to interrupt interleukin 6 signal transduction in multiple myeloma.
Electrophoretic mobility shift assays confirmed the involvement of NF-kappa B activation in regulating MM adhesion-induced IL-6 transcription in BMSCs.
Anti-IL-6 antibody and IL-6 antisense oligonucleotide suppressed the IL-6 stimulated myeloma cell proliferation, indicating that IL-6 induced the myeloma cell proliferation via an autocrine loop.
These results therefore suggest that anti-Fas MoAb-induced apoptosis in MM cells is associated with activation of SAPK, and that IL-6 may both inhibit apoptosis and modulate SAPK activity.