Protein Arginine Methyltransferase 1 (PRMT1) Selective Inhibitor, TC-E 5003, Has Anti-Inflammatory Properties in TLR4 Signaling

• Published in: International journal of molecular sciences Vol. 21; no. 9; p. 3058
• Main Authors: Kim, Eunji, Jang, Jiwon, Park, Jae Gwang, Kim, Kyung-Hee, Yoon, Keejung, Yoo, Byong Chul, Cho, Jae Youl
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.04.2020; MDPI
• Subjects: Acetamides - chemistry; Acetamides - pharmacology; Activator protein 1; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; AP-1; Arginine; c-Jun protein; Cell Line; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Cytotoxicity; Exploration; Gene expression; Gene Expression Regulation - drug effects; HEK293 Cells; Humans; Hypoxia; Inflammation; Inhibitors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Kinases; Lipopolysaccharides; Lipopolysaccharides - adverse effects; Mice; Molecular Structure; NF-κB; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nuclear transport; Oxidative stress; Oxidative Stress - drug effects; Pathogens; Phosphorylation; Polymerase chain reaction; Prostaglandin endoperoxide synthase; Protein arginine methyltransferase; protein arginine methyltransferase 1 (PRMT1); Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Proteins; RAW 264.7 Cells; Signal transduction; Signal Transduction - drug effects; TC-E 5003; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription factors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; NF-κB; protein arginine methyltransferase 1 (PRMT1); TC-E 5003; inflammation; AP-1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21093058

Protein arginine methyltransferase 1 (PRMT1) is the most predominant PRMT and is type I, meaning it generates monomethylarginine and asymmetric dimethylarginine. PRMT1 has functions in oxidative stress, inflammation and cancers, and modulates diverse diseases; consequently, numerous trials to develop PRMT1 inhibitors have been attempted. One selective PRMT1 inhibitor is -(Sulfonyldi-4,1-phenylene)bis(2-chloroacetamide), also named TC-E 5003 (TC-E). In this study, we investigated whether TC-E regulated inflammatory responses. Nitric oxide (NO) production was evaluated by the Griess assay and the inflammatory gene expression was determined by conducting RT-PCR. Western blot analyzing was carried out for inflammatory signaling exploration. TC-E dramatically reduced lipopolysaccharide (LPS)-induced NO production and the expression of inflammatory genes (inducible NO synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α and interleukin (IL)-6) as determined using RT-PCR. TC-E downregulated the nuclear translocation of the nuclear factor (NF)-κB subunits p65 and p50 and the activator protein (AP)-1 transcriptional factor c-Jun. Additionally, TC-E directly regulated c-Jun gene expression following LPS treatment. In NF-κB signaling, the activation of IκBα and Src was attenuated by TC-E. Taken together, these data show that TC-E modulates the lipopolysaccharide (LPS)-induced AP-1 and NF-κB signaling pathways and could possibly be further developed as an anti-inflammatory compound.