About this Journal Submit a Manuscript Table of Contents
BioMed Research International
Volume 2013 (2013), Article ID 580135, 8 pages
http://dx.doi.org/10.1155/2013/580135
Research Article

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

1Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea
2Clinical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea
3Hematology and Medical Oncology, Dongguk University Ilsan Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-773, Republic of Korea
4Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea
5Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea

Received 7 June 2013; Revised 15 August 2013; Accepted 16 August 2013

Academic Editor: Susanne Saussele

Copyright © 2013 Chansu Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

IL-6 and TNFα were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNFα than those with MM in plateau phase. TNFα increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNFα promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNFα treatments induce MEK and AKT phosphorylation. TNFα-stimulated IL-6 production was abolished by inhibition of JAK2 and IKKβ or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNFα increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF-κB activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNFα-mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.