Soluble IL-6 Receptor Synergistically Stimulates the Growth of Multiple Myeloma with IL-6 and Confers Resistance to Bortezomib.

Proinflammatory cytokines including Interleukin-6 (IL-6), TNFa, and IL-8, involved in a variety of cellular responses including proliferation, differentiation, and inflammatory processes. They play a pivotal role in the pathogenesis of multiple myeloma (MM). Elevated IL-6 and souble IL-6 receptor (sIL-6R) levels have been found in MM patients indicating that its production is not only coordinated as part of a disease progression but also strongly associated with outcome of anti-cancer therapy. Even though Bortezomib, one of proteosome inhibitors, is known to effectively induce the apoptosis of U266 myeloma cells via caspase-dependent pathway and inactivation of NF-kB, these apoptotic effects by Bortezomib could be decreased in U266 myeloma cells exposed to various proinflammatory cytokines. However, roles of IL-6 and sIL-6R in the progression of MM and response to anti-cancer treatment still remain to be explored. In this study, ELISA assay showed higher levels of IL-6, sIL-6R, and IL-8 in bone marrow plasma of MM patients compared to control group, which is the similar results of other investigators. Bortezomib-induced apoptotic effect in U266 myeloma cells was reduced by treatment of IL-6. This Bortezomib-induced apoptotic effect was more reduced in U266 myeloma cells following combined treatment with IL-6 and sIL-6R, although sIL-6R only did not exert on apoptotic effect. Caspase-3 activity by Bortezomib treatment decreased when U266 cells exposed to combined IL-6 and sIL-6R. In addition, U266 cells treated with combined IL-6 and sIL-6R synergically activated the phosphorylation of STAT-3 and ERK resulting in prolong survival of U266 cells. Phosphorylation of STAT-3 and ERK in U266 myeloma cells following combined treatment of IL-6 and sIL-6R did not affect by Bortexomib treatment. These results suggest that the levels of IL-6 and sIL-6R in bone marrow plasma may strongly be associated with clinical outcome of Bortezomib treatment in MM patients.