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-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Zhang, Yiheng¹  de Boer, Miriam¹  van der Wel, Ezra J.¹  Van Eck, Miranda¹  Hoekstra, Menno¹ 

[1] Leiden Univ, Leiden Acad Ctr Drug Res, Div BioTherapeut, Einsteinweg 55, NL-2333 CC Leiden, Netherlands

关键词: Gene expression;    Pro-inflammatory cytokines;    Thioglycollate-induced peritonitis;    LPS;    CARM1;   

DOI  :  10.1016/j.bbadis.2021.166212

来源: Elsevier

【 摘 要 】

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-kappa B-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)-1 beta, IL-6, IL-12p40, and tumor necrosis factor- a in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing proinflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6C(low)CD206(hi) to a pro-inflammatory LY6C(hi)CD206(low) 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-.B-based inflammatory diseases.

【 授权许可】

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