Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea.
Biomed Res Int. 2013;2013:580135. doi: 10.1155/2013/580135. Epub 2013 Sep 16.
IL-6 and TNF α 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 TNF α than those with MM in plateau phase. TNF α increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNF α promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNF α treatments induce MEK and AKT phosphorylation. TNF α -stimulated IL-6 production was abolished by inhibition of JAK2 and IKK β or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNF α 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- κ B activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNF α -mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.
与正常对照相比，活动期多发性骨髓瘤（MM）患者的骨髓抽吸样本中白细胞介素 6（IL-6）和肿瘤坏死因子 α（TNF α）明显升高。此外，与处于平台期的 MM 患者相比，进展性侵袭性疾病的 MM 患者的 IL-6 和 TNF α 水平明显更高。TNF α 增加 MM 细胞产生白细胞介素 6（IL-6）。然而，TNF α 通过信号通路促进 MM 细胞分泌 IL-6 的详细机制在很大程度上尚不清楚。在我们的研究中，我们发现 TNF α 处理诱导 MEK 和 AKT 磷酸化。通过抑制 JAK2 和 IKK β 或针对 TNF 受体（TNFR）的小干扰 RNA（siRNA）而不是通过 MEK、p38 和 PI3K 抑制剂，可消除 TNF α 刺激的 IL-6 产生。此外，TNF α 增加 STAT3（丝氨酸 727）的磷酸化，包括 c-Myc 和细胞周期蛋白 D1。三种不同类型的 JAK 抑制剂可降低上述通路的激活。总之，阻断 JAK/STAT 介导的 NF- κ B 激活在控制 MM 细胞生长方面非常有效，因此，TNF α 介导的 IL-6 分泌抑制剂可能成为多发性骨髓瘤患者的一种新的潜在治疗药物。
