CD40 LIGAND TRIGGERED INTERLEUKIN-6 SECRETION IN MULTIPLE-MYELOMA

Previous studies have suggested that interleukin-6 (IL-6) may mediate growth of multiple myeloma (MM) in either an autocrine or paracrine gr owth mechanism. However, those molecules which can trigger IL-6 secret ion either by tumor cells or non-MM marrow cells are not well characte rized. In the present study, we have examined the expression and funct ional 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 CD 40 ligand transfectant (CD40LT) cells increased (>30%) cell surface CD 80, CD18, CD11a, CD11b, and CD11c expression on MM cell lines. Culture with either fresh or paraformaldehyde fixed NIH3T3 CD40LT cells upreg ulates IL-6 secretion in MM cells and MM-derived cell lines, as well a s normal and MM bone marrow mononuclear cells (BMMCs), BMSCs, and BMSC lines; this effect can be specifically blocked by anti-CD40 monoclona l antibody (MoAb). BMMCs and BMSCs from patients with MM secreted sign ificantly more IL-6 than those from healthy donors (n = 3, P < .001); moreover, after stimulation using CD40L, IL-6 secretion was fourfold g reater (n = 3, P < .001) from MM BMMCs and BMSCs than from normal BMMC s and BMSCs. Myeloma (CD38(+)CD45RA(-)) cells and non-MM (CD38(+)CD45R A(+), 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 -CD40 MoAb 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 auto crine and paracrine growth mechanisms may be possible in MM. (C) 1995 by The American Society of Hematology.