Purpose: Chronic glomerulonephritis (CGN) is a disease that occurs in the glomeruli. The mechanism of CGN is thought to be involved in a range of inflammatory responses. MicroRNA-339-5p (miR-339-5p) has been reported to be involved in inflammatory responses in many diseases. However, the role of miR -339-5p in CGN remains unclear. The purpose of this study was to investigate the role of miR-339-5p in lipopolysaccharide (LPS) -induced nephritis injury in vitro. Methods: The RNA expression of miR-339-5p and Syk/Ras/c-Fos pathway was detected by qRT-PCR, the protein expression and localization of Syk/Ras/c-Fos pathway was detected by western blot and immunofluorescence (IF), and the targeted binding of miR-339-5p to Syk was detected by double luciferase. Cell viability and cell cycle were detected by cell counting kit-8 (CCK-8) and flow cytometry. The concentrations of inflammatory cytokines IL-1β, IL-10, IL-6 and TNF-α were detected by enzyme linked immunosorbent assay (ELISA). Results: LPS increased HBZY-1 cell viability, decreased G2 phase, promoted cell proliferation and inflammatory cytokine release. Overexpression of miR-339-5p can inhibit HBZY-1 cell viability, decreased the expression of Syk/Ras/c-Fos signaling pathway, down-regulate the expression level of inflammatory cytokines, increase G2 phase, and inhibit cell proliferation.Conclusion: miR-339-5p inhibits the proliferation and inflammation of rat mesangial cell through Syk/Ras/c-Fos signal pathway.
The immune-response gene 1 (IRG1) plays a key role in anti-pathogen defense, as deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection, and decreased survival1, 2. IRG1 transcription is rapidly induced by pathogen infection and inflammatory conditions primarily in cells of myeloid lineage3. IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate to produce the anti-inflammatory metabolite itaconic acid (ITA)4. Several molecular processes are affected by ITA, including succinate dehydrogenase (SDH) inhibition5, resulting in succinate accumulation and metabolic reprogramming6, 7, and alkylation of protein cysteine residues, inducing the electrophilic stress response mediated by NRF2 and IκBζ8, 9 and impairing aerobic glycolysis10. However, the mechanisms by which ITA exerts its profound anti-inflammatory effect still remains to be fully elucidated. Here, we show that ITA is a potent inhibitor of the TET family DNA dioxygenases, which catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) during the process of active DNA demethylation. ITA binds to the same site of α-ketoglutarate (α-KG) in TET2, inhibiting its catalytic activity. Lipopolysaccharides (LPS) treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals TET2 is a major target of ITA in suppressing LPS-induced genes, including those regulated by NF-κB and STAT signaling pathways. In vivo, ITA decreases 5hmC, reduces LPS-induced acute pulmonary edema and lung and liver injury, and protects mice against lethal endotoxaemia in a manner that is dependent on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory response.
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