REGULATION OF INTERLEUKIN-6 IN MULTIPLE-MYELOMA AND BONE-MARROW STROMAL CELLS

We and others have shown that some freshly isolated multiple myeloma ( MM) cells and derived cell lines express interleukin 6 (IL-6) receptor s and proliferate in vitro in response to IL-6; a subset of MM cells a lso expresses IL-6 mRNA, is intracytoplasmic IL-6 positive and secrete s IL-6, We have shown that MM cells express the cell surface adhesion molecules CD29/CDw49d(VLA-4), CD18/CD11a(LFA-1) and CD44, and may loca lize to marrow via specific adherence to both extracellular matrix pro teins and to bone marrow stromal cells (BMSCs). MM cell adhesion trigg ers IL-6 secretion by normal and MM BMSCs and related IL-6-mediated tu mor cell growth, Our attempts to block MM I cell adhesion to BMSC-indu ced IL-6 secretion by using antibodies to CD29/CDw49d, CD18/11a, and/o r CD44 demonstrated minimal effects, suggesting that another ligand-re ceptor interaction triggers IL-6 secretion when MM cells and BMSCs are juxtaposed, Both MM cells and BMSCs express CD40, Triggering of MM ce lls and BMSCs via CD40 upregulates IL-6 secretion in both MM cells and MM-derived cell lines, as well as BMSCs and BMSC lines, suggesting th e possibility of both autocrine and paracrine MM cell growth triggered via CD40, Finally, experiments using the LP 101 BMSC line transiently transfected with IL-6 promoter fragments linked to chloramphenicol ac etyltransferase reporter gene demonstrate that adhesion of MM cells in duces IL-6 gene transcription in BMSCs, which is conferred via the NF- kappa B binding motif, Further characterization of mechanisms of IL-6 regulation in MM cells and BMSCs may provide new therapeutic strategie s based upon interruption of IL-6-mediated autocrine and paracrine tum or cell growth.