Potential Crosstalk of Interleukin-6-Heme Oxygenase-1 Dependent Mechanism Involved in Resistance to Lenalidomide in Multiple Myeloma Cells

Interleukin-6 (IL-6), as one of the most important multiple myeloma (MM) survival factors, has been verified to determine poor prognosis of MM. IL-6 mainly originates from paracrine of bone marrow stromal cells and autocrine of MM cells. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. The HO-1 expression levels in bone marrow CD138⁺ cells of MM patients, which were significantly higher than those of healthy donors, were positively correlated with serum IL-6 levels and intracellular IL-6 mRNA expression levels. Cultivating U266 and CD138⁺ cells with exogenous IL-6 in vitro induced high HO-1 expressions and allowed them to resist lenalidomide, probably because IL-6 activated the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Without IL-6 co-culture, on the other hand, up-regulating HO-1 expressions in U266 cells and bone marrow CD138⁺ cells from MM patients significantly up-regulated the mRNA expression level of IL-6 and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced of p38 MAPK phosphorylation. Down-regulating HO-1 expression sensitized U266 and CD138⁺ cells toward lenalidomide. Therefore, we postulated that HO-1 predominantly controlled IL-6 paracrine and autocrine, and that IL-6 in bone marrow microenvironment of MM patients stimulated MM cells to highly express HO-1 and to resist lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, thus further augmenting the drug resistance and exacerbating the disease. This study provides valuable experimental evidence for using HO-1 as a possible marker for MM prognosis and drug resistance and as a potential treatment target.