Role of Interleukin‐6 in the Pathogenesis of Multiple Myeloma

Abstract

Multiple myeloma (MM) is a currently incurable disease caused by the proliferation of malignant plasma cells. Although the pathogenesis of the disease still remains unclear, recent research in the biology of MM has produced new insights into the factors that control the growth and survival of myeloma cells. Among the growth factors, interleukin-6 (IL-6) has an essential role. Evidence suggests that IL-6 is not only a growth factor, but also a survival factor in MM, inhibiting apoptosis in myeloma cells. IL-6 interacts with several factors which are involved in the pathogenesis of MM, such as adhesion molecules, tumour suppressor genes and oncogenes. Considering the essential role of IL-6, it could serve as a target for new therapeutic interventions. Neutralizing the effect of IL-6 may result in a regression of tumour progression.

Toll-like receptors mediate proliferation and survival of multiple myeloma cells

“…7,34 Moreover, Pam 3 Cys could replace IL-6 in long-time cultures of the IL-6-dependent cell lines OH-2 and partially for ANBL-6. In addition, LPS was found to induce proliferation and to be a substitute for IL-6 in a long-time culture of ANBL-6 cells.…”

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

“…The choice to combine farnesyl transferase inhibition with proteasome inhibition stems from the observation that both pathways appear to be nonoverlapping and that an agent such as lonafarnib could inhibit interleukin-6 (IL-6)-mediated signaling, 14 a known survival pathway for myeloma cells. 15,16 In this report, we present data that demonstrate significant and synergistic myeloma-cell death when bortezomib and lonafarnib are added in combination at low, clinically achievable doses and that the combination results in brisk caspase 3, 8, and 9 cleavage, with rapid down-regulation of phospho-AKT (p-AKT). Additionally, we have demonstrated that order of addition is critically important, and suboptimal sequencing results in less down-regulation of p-AKT.…”

Expression of Interleukin-6, Interleukin-6 Receptor (gp80), and the Receptor's Signal-Transducing Subunit (gp130) in Human Normal Pituitary Glands and Pituitary Adenomas

“…The effect of IL-6 appears to be mediated through its membrane receptor, IL-6R, and binding of IL-6 to its receptor leads to the homodimerization of gp130 and then to the activation of signal-transducing tyrosine kinases (5, 6, 18). IL-6 has been reported as an autocrine and/or paracrine growth factor in several tumors (3,4,(7)(8)(9) and is known to induce the secretion or release of GH, PRL, ACTH, and LH/FSH in rat pituitary glands in vivo and/or in vitro (10,11). Several groups have examined the expression of IL-6 protein and mRNA and gp80mRNA in human normal pituitary glands and pituitary adenomas (13,14,19,20).…”

“…Although IL-6 has been shown to act as an autocrine growth factor in several tumors and is expressed by a variety of tumors (7)(8)(9), the expression of IL-6R has not been clarified in human pituitary adenomas. In the pituitary gland, many studies have demonstrated that IL-6 stimulates the release of PRL, GH, LH, and ACTH in vitro (10,11).…”