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PRMT4 inhibitor TP-064 inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo and induces peritonitis-associated neutrophilia in vivo
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2021-07-24 , DOI: 10.1016/j.bbadis.2021.166212
Yiheng Zhang 1 , Miriam de Boer 1 , Ezra J van der Wel 1 , Miranda Van Eck 1 , Menno Hoekstra 1
Affiliation  

Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo.

Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (−50%, P < 0.05) and the cyclin-dependent kinases 2 (−50%, P < 0.05) and 4 (−30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes.

In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases.



中文翻译:

PRMT4 抑制剂 TP-064 在体外和体外抑制促炎巨噬细胞脂多糖反应并在体内诱导腹膜炎相关的中性粒细胞增多

先前的体外研究表明,蛋白质精氨酸N-甲基转移酶 4 (PRMT4) 是一系列细胞活动的共激活剂,包括 NF-κB 调节的促炎反应。在这里,我们研究了 PRMT4 抑制剂 TP-064 治疗对体外和体内巨噬细胞炎症的影响。

将 RAW 264.7 单核细胞/巨噬细胞暴露于 TP-064 与脂多糖攻击后促炎细胞因子的产生显着减少有关。类似地,从用 TP-064 处理的野生型小鼠中分离的巯基乙酸盐诱导的腹膜细胞显示出降低的 mRNA 表达水平和促炎介质白细胞介素 (IL)-1β、IL-6、IL-12p40 和肿瘤坏死因子-α 的细胞因子产生对脂多糖暴露的反应。然而,TP-064 处理的小鼠在暴露于巯基乙酸盐 5 天后表现出持续的促炎性腹膜炎,这从腹膜巨噬细胞极化状态从抗炎性 LY6CCD206 hi转变为促炎性 LY6C hi CD206 可见一斑低的表型。此外,经 TP-064 处理的小鼠在腹膜以及血液中(高 7 倍;P  < 0.001)和主要器官(如肾脏和肝脏)积累(激活)中性粒细胞,而没有明显的组织毒性。TP-064 治疗下调了 PRMT4 靶基因葡萄糖-6-磷酸酶催化亚基 (-50%, P  < 0.05) 和细胞周期蛋白依赖性激酶 2 (-50%, P < 0.05) 和 4 (- 30%,P < 0.05),表明 PRMT4 在肝细胞中也有直接转录作用。

总之,我们已经证明 PRMT4 抑制剂 TP-064 在体内诱导腹膜炎相关的中性粒细胞增多,并在体外和体外抑制促炎巨噬细胞脂多糖反应。我们的研究结果表明,TP-064 可能用于治疗基于 NF-κB 的炎症性疾病。

更新日期:2021-07-28
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