MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT

Zhang, Jie; Zhang, Xiaofen; Tang, Chenxi; Chen, Yishu; Zhang, Yuwei; Yu, Mengli; Lü, Chao; Li, Meng; Li, Sha; Lin, Bingru; Zhang, Tiantian; Song, Xiaoling; Yu, Chaohui; Wu, Hao; Shen, Zhe

doi:10.1016/j.redox.2022.102469

Cited by 33 publications

(15 citation statements)

References 52 publications

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“…Human colonic mucosal epithelial cell was purchased from Procell (CP‐H040, Wuhan, China) and cultured in growth medium supplemented with 10% fetal bovine serum in an incubator with 5% CO 2 at 37°C. The colonic epithelial cells were treated with 100 ng/mL TNF‐α for 24 h to mimic the in vitro condition of UC 25 and transfected with plasmids including sh‐NC, sh‐IRF4, empty pcDNA3.1, and pcDNA3.1‐IRF4 using Lipofectamine 3000 (Invitrogen) according to the manufacturer's instructions. All these vectors were commercially available from GenePharma (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6‐dependent STAT3 pathway

Wang,

Wu,

Huang

et al. 2024

Environmental Toxicology

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Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation. An increasing body of evidence shows that macrophages play an important role in the pathogenesis of UC. Interferon regulatory factor 4 (IRF4) is crucial for the development of autoimmune diseases via regulating immune cells. This research was designed to explore the function of IRF4 in UC and its association with macrophage polarization. The in vitro model of UC was established by stimulating colonic epithelial cells with tumor necrosis factor α (TNF‐α). A mouse model of UC was constructed by injecting C57BL/6 mice with dextran sulfate sodium salt. Flow cytometry was used to assess percentage of CD11b+CD86+ and CD11b+CD206+ cells in bone marrow macrophages. Occult blood tests were used to detect hematochezia. Hematoxylin and eosin staining assay was used to assess colon pathological changes. Enzyme‐linked immunosorbent assay (ELISA) was used to detect concentrations of inflammatory cytokines. The interaction of IRF4 and B‐cell lymphoma 6 (Bcl6) was confirmed using GST pull‐down and coimmunoprecipitation assays. Our findings revealed that IRF4 promoted cell apoptosis and stimulated M1 macrophage polarization in vitro. Furthermore, IRF4 aggravated symptoms of the mouse model of UC and aggravated M1 macrophage polarization in vivo. IRF4 negatively regulated Bcl6 expression. Downregulation of Bcl6 promoted apoptosis and M1 macrophage polarization in the presence of IRF4 in vitro and in vivo. Moreover, Bcl6 positively mediated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In conclusion, IRF4 aggravated UC progression through promoting M1 macrophage polarization via Bcl6/JAK2/STAT3 pathway. These findings suggested that IRF4 might be a good target to competitively inhibit or to treat with UC.

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Section: Methodsmentioning

confidence: 99%

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6‐dependent STAT3 pathway

Wang,

Wu,

Huang

et al. 2024

Environmental Toxicology

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“…Isolated colonic crypts were resuspended in DMEM/F12 medium, counted and resuspended in colonic organoid growth medium and matrix gel (Corning) at a 1:1 ratio. [ 44 ] The medium was changed every other day, and after 7 days, the organoid was stimulated with 150 ng/ml mouse recombinant TNF-α (PeproTech) for 24 h. [ 45 ] All cells were cultured and maintained at 37 °C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota

Cheng,

Xu,

Sun

et al. 2023

Preprint

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BACKGROUND & AIMS: E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Our aim was to investigate the role of ASB3 in gut epithelium inflammation. METHODS: ASB3 was quantified in the lesions of IBD patients using Western blotting, qPCR and immunohistochemistry. We treated wild-type (WT) and ASB3-/- FVB-N mice and their derived colonic organoids with dextran sulfate sodium (DSS) or TNF-α as models of colitis and assessed inflammation onset, transcriptome, microbiome and ubiquitination modifications. RESULTS: ASB3-/- mice are resistant to DSS-induced colitis. IκBα phosphorylation levels and production of pro-inflammatory factors IL-1β, IL-6, and TNF-α were reduced in colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotic clearance of the microbiota. In addition, ASB3 specifically interacts with TRAF6 and degrades it via the proteasomal pathway. Further analysis revealed that ASB3 enhances K48-linked polyubiquitination of TRAF6 through the interaction of its SOCS box (SOCX) domain with the TRAF6 C-terminal domain. CONCLUSIONS: ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors production by disrupting the TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis.

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“…The role of 3-MST in human ulcerative colitis, Crohn’s disease, and animal models was evaluated. Very low expression of 3-MST was observed in colonic samples with a marked increase in the expression of inflammatory cytokines and apoptotic factors along with ROS markers [ 114 ]. 3-MST exerts its protective effect by reducing AKT phosphorylation and increasing AKT expression, which regulates the apoptosis process and protects intestinal epithelial cells from inflammatory mediators.…”

Section: Role Of 3-mst In Diseasementioning

confidence: 99%

Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease

et al. 2023

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3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen sulfide is also produced through cystathionine beta-synthase and cystathionine gamma-lyase, along with 3-MST, and is known to alleviate a variety of illnesses such as cancer, heart disease, and neurological conditions. The importance of cystathionine beta-synthase and cystathionine gamma-lyase in hydrogen sulfide biogenesis is well-described, but documentation of the 3-MST pathway is limited. This account compiles the current state of knowledge about the role of 3-MST in physiology and pathology. Attempts at targeting the 3-MST pathway for therapeutic benefit are discussed, highlighting the potential of 3-MST as a therapeutic target.

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MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT

Cited by 33 publications

References 52 publications

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6‐dependent STAT3 pathway

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6‐dependent STAT3 pathway

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota

Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease

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