Interleukin 6 (IL-6) is involved in the proliferation and differentiation of plasmablastic cells72-74 into Ig-secret-ing mature plasma cells.75-77 This process is also dependent on the interaction between fibronectin, produced by bone marrow stromal cells (BMCLs), and receptor VLA-4 and VLA-5 on bone marrow Ig-secreting plasma cells.77

In multiple myeloma, IL-6 is a major autocrine and paracrine growth factor.78-82 This is based on in vitro and in vivo studies, which have shown that anti-IL-6 antibody almost completely inhibits proliferation of myeloma cells. Bone marrow stroma is the predominant source of IL-6 and its secretion is upregulated by transforming growth factor p, IL-1p, and IL-10, which is produced by BMCLs and myeloma cells.83 IL-6 correlates with disease activity in plasma cell dyscrasia.8485 Higher levels of serum IL-6 and soluble IL-6 receptors are associated with disease progression and poor prog-nosis.84-86 Soluble IL-6 receptor/IL-6 complex activates gp130 and increases the IL-6 sensitivity of myeloma cell lines.87

Activation of the gp130 IL-6 transducer is a key signal for myeloma proliferation. It mediates the IL-6 as well as other myeloma growth factors/cytokines including leukocyte inhibitory factor, OSM, IL-11, and CNTF.

Other cytokines interact with IL-6 and influence myeloma growth. IL-1a, IL-2, IL-4, and IL-10 induce partial differentiation of B cells to normal plasmablastic cells. Interferon alpha has differing effects on myeloma, depending on the surface receptors on myeloma cells. It stimulates IL-6-dependent proliferation in some myeloma cell lines, but prolongs the plateau phase in patients responsive to therapy. Interferon gamma is a potent inhibitor of myeloma proliferation via down-regulation of IL-6 receptor complex.

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