Human C15orf39 Inhibits Inflammatory Response via PRMT2 in Human Microglial HMC3 Cell Line.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Inflammation*/metabolism ; Inflammation*/genetics ; Inflammation*/pathology ; Interleukin-6*/metabolism ; Interleukin-6*/genetics ; Lipopolysaccharides*/pharmacology ; Microglia*/metabolism ; Microglia*/drug effects ; Protein-Arginine N-Methyltransferases*/metabolism ; Protein-Arginine N-Methyltransferases*/genetics ; Tumor Necrosis Factor-alpha*/metabolism; Humans ; Cell Line ; Interferon-gamma/metabolism ; Interferon-gamma/pharmacology ; NF-kappa B/metabolism ; Open Reading Frames ; Signal Transduction ; Chromosomes, Human, Pair 15

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.

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KZ202210025035 R&D Program of Beijing Municipal Education Commission; 82071758 and 32270933 National Natural Science Foundation of China

Keywords: C15orf39; NF-κB; PRMT2; inflammation; microglia

82115-62-6 (Interferon-gamma)
0 (Interleukin-6)
0 (Lipopolysaccharides)
0 (NF-kappa B)
EC 2.1.1.319 (PRMT2 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
0 (Tumor Necrosis Factor-alpha)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240703

20240703

PMC11173073

10.3390/ijms25116025

38892217