Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production

We studied the role of interleukin (IL)-1 beta in patients with multiple myeloma. By in situ hybridization and immunochemistry, myeloid and megakaryocytic cells expressed high levels of the IL-1 beta gene and produced IL-1 beta. Myeloma cells less potently expressed the IL-1 beta gene and IL-1 beta protein. IL-1 beta gene expression was not constitutive since it was detected in the bane marrow myeloma cells of two patients, unlike circulating tumoural cells. In addition, nine myeloma cell lines failed to express the IL-1 beta gene and this expression could not be induced by 12 different cytokines. We demonstrated that IL-1 was mainly responsible for IL-6 production in the tumoural environment through a PGE(2) loop. In fact, an IL-1 receptor antagonist (IL-1RA) blocked PGE(2) synthesis and IL-6 production by 80%; this blockage could be reversed by adding synthetic PGE(2). Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks PGE(2) synthesis. Taken together, these data emphasize the possibility of blocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 production, which is a major tumoural survival and proliferation factor.