Abstract
Multiple myeloma (MM) is a malignant plasma disease closely associated with inflammation. In MM bone marrow microenvironment, bone marrow stromal cells (BMSCs) are the primary source of interleukin-6 (IL-6) secretion, which promotes the proliferation and progression of MM cells. However, it is still unknown how the microenvironment stimulates BMSCs to secrete IL-6. Interleukin-32 (IL-32) is a newly identified pro-inflammatory factor. It was reported that in solid tumors, IL-32 induces changes in other inflammatory factors including IL-6, IL-10, and TNF-α. The aim of this study was to investigate the expression of IL-32 and the role of IL-32 in the MM bone marrow microenvironment. Our data illustrate that MM patients have higher expression of IL-32 than healthy individuals in both bone marrow and peripheral blood. We used ELISA and qRT-PCR to find that malignant plasma cells are the primary source of IL-32 production in MM bone marrow. ELISA and Western blot analysis revealed that recombinant IL-32α induces production of IL-6 in BMSCs by activating NF-κB and STAT3 signaling pathways, konckdown of IL-32 receptor PR3 inhibit this process. Knockdown of IL-32 by shRNA decreased the proliferation in MM cells that induced by BMSCs. In conclusion, IL-32 secreted from MM cells has paracrine effect to induce production of IL-6 in BMSCs, thus feedback to promote MM cells growth.
Highlights
Multiple myeloma (MM), characterized by the accumulation of malignant plasma cells and the production of monoclonal immunoglobulin, is an incurable malignant blood disease that originates from the B cell lineage and accounts for approximately 21% of deaths from hematological malignancies in the US [1,2,3]
We checked the expression of IL-32 in MM cell lines and human bone marrow stromal cells (BMSCs) using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA)
The results suggested that MM cell lines expressed IL-32
Summary
Multiple myeloma (MM), characterized by the accumulation of malignant plasma cells and the production of monoclonal immunoglobulin, is an incurable malignant blood disease that originates from the B cell lineage and accounts for approximately 21% of deaths from hematological malignancies in the US [1,2,3]. MM development is primarily dependent on the bone marrow (BM) microenvironment. Direct contact with cells in the BM microenvironment, such as bone marrow stromal cells (BMSCs), macrophages, osteoclasts and endothelial cells, induces MM cell growth, proliferation, invasion and metastasis, as do the cytokines and the chemokines in the microenvironment [4,5,6]. A history of infection, and other inflammatory diseases have a higher incidence of MM and monoclonal gammopathy of undetermined significance (MGUS) [7]. Researches showed that inflammatory mediators, such as interleukin www.impactjournals.com/oncotarget
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