WP1066 suppresses macrophage cell death induced by inflammasome agonists independently of its inhibitory effect on STAT3.
WP1066 suppresses macrophage cell death induced by inflammasome agonists independently of its inhibitory effect on STAT3.
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DOI：
10.1111/cas.13154
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发表时间：
2017-03
期刊：
影响因子：
5.7
通讯作者：
Takeda K
中科院分区：
文献类型：
--
作者：
Honda S;Sadatomi D;Yamamura Y;Nakashioya K;Tanimura S;Takeda K
化合物WP 1066最初是通过修饰AG 490的结构而合成的，其通过直接靶向Janus激酶（JAK）来抑制信号转导和转录激活因子3（STAT 3）的激活。WP1066对恶性胶质瘤和其他癌细胞的抗癌活性比AG 490更强，被认为是一种有前途的治疗剂。通过筛选靶向已知化合物的小文库，我们将WP 1066鉴定为NLRP 3炎性体激动剂诱导的巨噬细胞死亡的抑制剂，NLRP 3炎性体是一种细胞内蛋白复合物，用于加工促炎细胞因子白细胞介素（IL）-1 β。WP1066强烈抑制小鼠腹膜渗出液细胞和人白血病单核细胞THP-1细胞中由炎性体激动剂诱导的细胞死亡以及IL-1β的细胞外释放，所述人白血病单核细胞THP-1细胞通过PMA处理分化为巨噬细胞。然而，炎性体激动剂不增加STAT 3磷酸化，另一种JAK抑制剂ruxolitinib不抑制细胞死亡，尽管它强烈抑制基础STAT 3磷酸化。因此，WP 1066似乎抑制巨噬细胞死亡，而不依赖于其对STAT 3的抑制作用。相比之下，WP 1066本身诱导未分化THP-1细胞的死亡，这表明WP 1066以环境依赖性方式差异调节细胞死亡。与以前的研究结果一致，WP 1066诱导人胶质瘤A172和T98 G细胞死亡。然而，无论是ruxolitinib还是AG 490，前者完全抑制STAT 3磷酸化，诱导这些胶质瘤细胞的死亡。这些结果表明，WP1066靶向细胞死亡调节分子，而不是参与JAK-STAT 3信号传导的分子。
The compound WP1066 was originally synthesized by modifying the structure of AG490, which inhibits the activation of signal transducer and activator of transcription 3 (STAT3) by directly targeting Janus kinases (JAKs). WP1066 exhibits stronger anti‐cancer activity than AG490 against malignant glioma and other cancer cells and is regarded as a promising therapeutic agent. By screening a small library of target‐known compounds, we identified WP1066 as an inhibitor of macrophage cell death induced by agonists of the NLRP3 inflammasome, an intracellular protein complex required for the processing of the proinflammatory cytokine interleukin (IL)‐1β. WP1066 strongly inhibited cell death as well as extracellular release of IL‐1β induced by inflammasome agonists in mouse peritoneal exudate cells and human leukemia monocytic THP‐1 cells that were differentiated into macrophagic cells by treatment with PMA. However, inflammasome agonists did not increase STAT3 phosphorylation, and another JAK inhibitor, ruxolitinib, did not inhibit cell death, although it strongly inhibited basal STAT3 phosphorylation. Thus, WP1066 appears to suppress macrophage cell death independently of its inhibitory effect on STAT3. In contrast, WP1066 itself induced the death of undifferentiated THP‐1 cells, suggesting that WP1066 differentially modulates cell death in a context‐dependent manner. Consistent with previous findings, WP1066 induced the death of human glioma A172 and T98G cells. However, neither ruxolitinib nor AG490, the former of which completely suppressed STAT3 phosphorylation, induced the death of these glioma cells. These results suggest that WP1066 targets cell death‐modulating molecules other than those involved in JAK‐STAT3 signaling.