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 my eloma. By in situ hybridization and immunochemistry, myeloid and megakaryoc ytic cells expressed high levels of the IL-1 beta gene and produced IL-1 be ta. 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 detect ed in the bane marrow myeloma cells of two patients, unlike circulating tum oural 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 cytoki nes. We demonstrated that IL-1 was mainly responsible for IL-6 production i n 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%; t his blockage could be reversed by adding synthetic PGE(2). Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks P GE(2) synthesis. Taken together, these data emphasize the possibility of bl ocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 pro duction, which is a major tumoural survival and proliferation factor.