ArticleMolecular medicine (Cambridge, Mass.)2020
iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice.
Article in Molecular medicine (Cambridge, Mass.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 16 citations in OpenAlex.
- Interferon regulatory factors: the next prospective targets for tissue ischemia-reperfusion injury?Frontiers in immunology · 2026Review
- The Role of Interferon Regulatory Factors in Liver Diseases.International journal of molecular sciences · 2024Review
- Identification of chalcone analogues as anti-inflammatory agents through the regulation of NF-κB and JNK activation.RSC medicinal chemistry · 2024Article
- Key role of interferon regulatory factor 1 (IRF-1) in regulating liver disease: progress and outlook.Journal of Zhejiang University. Science. B · 2024Review
- Downregulation of iNOS/NO Promotes Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.Molecular cancer research : MCR · 2023Article
- The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation.International journal of molecular sciences · 2022Article
- Lipoxin alleviates oxidative stress: a state-of-the-art review.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Review
- New progress in understanding roles of nitric oxide during hepatic ischemia-reperfusion injury.World journal of hepatology · 2022Review
- PIAS1 Alleviates Hepatic Ischemia-Reperfusion Injury in Mice through a Mechanism Involving NFATc1 SUMOylation.Disease markers · 2022Article
- Ischemic Postconditioning Protects against Aged Myocardial Ischemia/Reperfusion Injury by Transcriptional and Epigenetic Regulation of miR-181a-2-3p.Oxidative medicine and cellular longevity · 2022Article
- Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction.Journal of enzyme inhibition and medicinal chemistry · 2021Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundIschemia and reperfusion (I/R) induces cytokines, and up-regulates inducible nitric oxide synthase (iNOS), interferon regulatory factor-1(IRF1) and p53 up-regulated modulator of apoptosis (PUMA), which contribute to cell death and tissue injury. However, the mechanisms that I/R induces IRF1-PUMA through iNOS/NO is still unknown.
methodsIschemia was induced by occluding structures in the portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver lobes for 60 min, and reperfusion was initiated by removal of the clamp. Induction of iNOS, IRF1 and PUMA in response to I/R were analyzed. I/R induced IRF1 and PUMA expression were compared between iNOS wild-type and iNOS knockout (KO) mice. Human iNOS gene transfected-cells were used to determine iNOS/NO signals targeting IRF1. To test whether HDAC2 was involved in the mediation of iNOS/NO-induced IRF1 transcriptional activities and its target gene (PUMA and p21) expression, NO donors were used in vitro and in vivo.
resultsIRF1 nuclear translocation and PUMA transcription elevation were markedly induced following I/R in the liver of iNOS wild-type mice compared with that in knock-out mice. Furthermore, I/R induced hepatic HDAC2 expression and activation, and decreased H3AcK9 expression in iNOS wild-type mice, but not in the knock-out mice. Mechanistically, over-expression of human iNOS gene increased IRF1 transcriptional activity and PUMA expression, while iNOS inhibitor L-NIL reversed these effects. Cytokine-induced PUMA through IRF1 was p53 dependent. IRF1 and p53 synergistically up-regulated PUMA expression. iNOS/NO-induced HDAC2 mediated histone H3 deacetylation and promoted IRF1 transcriptional activity. Moreover, treating the cells with romidepsin, an HDAC1/2 inhibitor decreased NO-induced IRF1 and PUMA expression.
conclusionsThis study demonstrates a novel mechanism that iNOS/NO is required for IRF1/PUMA signaling through a positive-feedback loop between iNOS and IRF1, in which HDAC2-mediated histone modification is involved to up-regulate IRF1 in response to I/R in mice.
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