文章：

JAK抑制剂AZD1480调节霍奇金淋巴瘤的增殖和免疫

The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma

原文发布日期：2011-12-02

DOI: 10.1038/bcj.2011.46

类型: Original Article

开放获取: 是

英文摘要：

Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μM) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μM) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL.

摘要翻译： 

据报道，Janus激酶（JAK）/信号转导与转录激活因子（STAT）通路的异常激活会促进霍奇金淋巴瘤（HL）中霍奇金和里德-斯特恩伯格细胞的增殖与存活。我们研究了JAK抑制剂AZD1480在HL衍生细胞系中的活性，并确定了其作用机制。低剂量（0.1-1μM）的AZD1480能有效抑制STATs磷酸化，但并未预期性地产生抗增殖效应，因为它激活了一个负反馈环路，导致JAK2及细胞外信号调节激酶1和2（ERK1/2）的磷酸化，并增加了上清液中IP-10、RANTES和白细胞介素（IL）-8的浓度。通过丝裂原活化细胞外信号调节激酶（MEK）抑制剂（UO126和PD98059）抑制ERK活性，增强了AZD1480的细胞毒活性。有趣的是，亚微摩尔浓度的AZD1480通过下调辅助性T细胞2型细胞因子和趋化因子（包括IL-13、胸腺活化调节趋化因子）以及免疫抑制性程序性死亡配体1和2的表面表达，显示出显著的免疫调节作用。较高浓度的AZD1480（5μM）通过抑制Aurora激酶诱导G2/M期阻滞和细胞死亡。我们的研究表明，AZD1480在HL细胞系中调节增殖和免疫，并为评估AZD1480单独或与MEK抑制剂联合在HL中的应用提供了机制依据。

原文链接：

The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma