Figure 1.

Mechanism of action of pro- and anti-inflammatory cytokines. IL-1, produced by various cell types in the BM microenvironment (i.e., fibroblasts, B lymphocytes), promotes PCs’ survival by stimulating IL-6 production. IL-2 is produced by CD8⁺ and CD4⁺ T lymphocytes and promotes the growth of T and NK cells but at the same time induces apoptosis of T cells; it also stimulates the cytotoxic action of NK cells against malignant PCs. IL-6 promotes the growth of MM PCs and resistance to apoptosis; IL-6 is secreted by BMSCs, monocytes, endothelial cells, macrophages and fibroblasts thanks to the action of TGF-β, TNF-α, VEGF, IL-1. IL-1 and TNF are potent inducers of IL-6 synthesis. In detail, they regulate IL-6 gene expression at the level of transcription, which is mediated by upregulation of NF-kB activation. IL-6 stimulates the production of APRIL and BAFF, which activate NF-kB, phosphatidylinositol-3 (PI-3) kinase/AKT and MAPK pathways, promoting MM cells’ survival. IL-8 has a pro-tumor function promoting angiogenesis and tumor invasion. IL-11 promotes tumor invasion and in particular bone damage. IL-12 stimulates the production of IFN-γ with both pro-inflammatory and anti-angiogenic roles and this inhibits the production of VEGF. IL-22 is produced by T lymphocytes, activates the innate immune system and also regulates cell proliferation and resistance to drug-induced cell death in MM cells. IL-27 has antitumor activity, causing increased proliferation and differentiation of T cells. IL-27 stimulates the expression of immune checkpoint inhibitor programmed death (PD)-1 or PD-L1 in different cell types (i.e., lymphocytes and dendritic cells) and increases NK cells’ activity. HSP and HSP90 are produced by macrophages/monocytes and promote MM cell survival through TNF-mediated and NF-kB signaling pathways.