A striking clinical feature of myeloma cells relates to their tendency to remain in the bone marrow environment until the very end stage of the disease. Although several of the molecules important in myeloma cell- stromal cell adhesion have been identified, little is known about the factors that regulate adhesion molecule expression/function in human myeloma cells. Because we have shown that IL-1beta is abnormally produced in virtually all myeloma patients and because IL-1beta has been shown to upregu1ate adhesion molecules in other cellular systems, we propose to investigate the role of IL-1beta on adhesion molecule expression and function. We hypothesize that the aberrant IL-1beta production upregulates adhesion molecules on either the myeloma cells or the marrow stromal cells, or both, and induces increased myeloma cell-stroma1 cell adhesion and paracrine IL-6 production. Using human myeloma cell lines, that differ with respect to IL-1beta expression in the SCID mouse model that mimics human disease, and freshly isolated bone marrow cells from patients with MGUS and MM to test this hypothesis, we propose to: 1) Study the in vivo effects of IL-1beta sense/antisense cDNAs on human myeloma cell lines in the SCID mouse model; 2) Determine the adhesion molecule phenotype of IL-1beta positive and negative plasma cells from patients with MGUS or myeloma and investigate the effects of IL-1beta, anti-IL-1beta antibody, soluble IL-1 receptors, IL-1 receptor antagonist, or an interleukin- 1beta converting enzyme (ICE) chemical inhibitor on the adhesion molecule expression of myeloma cells from patients; 3) Investigate the effects of IL- 1beta, anti-IL-1beta antibody, soluble IL-I receptors, IL- l receptor antagonist, or an ICE chemical inhibitor on the adhesion of patient myeloma cells to bone marrow stromal cells and on IL-6 production. Collectively, these proposed experiments will provide critical information in myeloma toward the understanding of the role of IL-1beta in adhesion molecule expression/function and disease pathology.
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