TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells.
TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells.
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DOI：
10.1155/2013/580135
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发表时间：
2013
影响因子：
--
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Lee C;Oh JI;Park J;Choi JH;Bae EK;Lee HJ;Jung WJ;Lee DS;Ahn KS;Yoon SS
活动性多发性骨髓瘤（MM）患者骨髓穿刺液中IL-6和TNFα水平显著高于正常对照组。MM患者中，侵袭性疾病组IL-6和TNFα水平明显高于平台期组。TNFα增加MM细胞产生白细胞介素-6（IL-6）。然而，TNFα促进MM细胞分泌IL-6的信号通路的详细机制在很大程度上是未知的。在我们的研究中，我们发现TNFα处理诱导MEK和AKT磷酸化。抑制JAK 2和IKKβ或靶向TNF受体（TNFR）的小干扰RNA（siRNA）可消除TNFα刺激的IL-6产生，但MEK、p38和PI 3 K抑制剂不能消除。此外，TNFα增加了STAT 3（ser 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抑制剂降低了上述途径的激活。总之，阻断JAK/STAT介导的NF-κB活化在控制MM细胞生长方面是高度有效的，因此，TNFα介导的IL-6分泌抑制剂将是多发性骨髓瘤患者的潜在新治疗剂。
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.