TNFα Mediated IL-6 Secretion Was Regulated by JAK/STAT Pathway but Not by MEK Phosphorylation and AKT Phopshorylaton In U266 Multiple Myeloma Cells

Abstract 1930

Serum levels of IL-6 and TNF-a were significantly increased in patients with active multiple myeloma (MM) when compared with normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNFa than those with MM in plateau phase. However, the detailed mechanisms involving TNFa-mediated cell signaling pathways resulting in increased IL-6 secretion from MM cells are largely unknown. In our study, we found that MEK and AKT phosphorylation was induced by TNFa treatments. TNFa increased MM-derived Interleukin-6 (IL-6) production. TNF-a-stimulated IL-6 production was abolished by inhibition of JAK2 and IKKa, but not of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor (TNFR). Also, TNFa increased phosphorylation of STAT-3, -5 including c-Myc and cyclinD1. Three different types of JAK inhibitors decreased the activation of the above pathways. In conclusion, blockage of JAK/STAT mediated NF-kB activation was highly effective in controlling the growth of MM cells and consequently, a new inhibitor of TNFa mediated IL-6 secretion may be a potential new therapeutic agent for MM.