{"title":"The IL-1β/STAT1 Axis inhibits STAT3 function via Sequestration of the transcriptional activator GLIS2, leading to postoperative vascular dysfunction","authors":"","doi":"10.1016/j.intimp.2024.113372","DOIUrl":null,"url":null,"abstract":"<div><div>Surgery-induced endothelial dysfunction is crucial in thrombus formation, driven by the release of inflammatory mediators due to surgical trauma. The STAT family, known for amplifying inflammatory responses via cytokine activation, plays an unclear role in the signaling mechanisms from surgery to molecular activation, and their regulatory effects on inflammation vary. This study aimed to identify key signaling pathways responsible for vascular dysfunction post-surgery and to discover potential targets for predicting or preventing thrombosis. To explore this, endothelial cells were co-cultured with post-surgical trauma serum and analyzed using various assays. Bioinformatics analysis linked surgical trauma with pathways involving thrombosis, interleukins, cytokines, and STAT signaling. Elevated inflammatory mediators were observed in mouse serum post-surgical trauma, with IL-6 activating STAT3 to enhance endothelial proliferation, while IL-1β activated STAT1, inhibiting STAT3′s effects. Gli-similar 2 (GLIS2), a novel coactivator of STAT3, was found to regulate STAT transcription. STAT1, however, inhibited GLIS2′s interaction with STAT3, suppressing STAT3′s role in endothelial proliferation. The study concludes that IL-1β-triggered STAT1 activation impedes GLIS2-STAT3 interaction, reducing STAT3′s transcriptional activity and leading to endothelial dysfunction, presenting new targets for preventing post-surgical trauma endothelial dysfunction and thrombosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576924018940","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Surgery-induced endothelial dysfunction is crucial in thrombus formation, driven by the release of inflammatory mediators due to surgical trauma. The STAT family, known for amplifying inflammatory responses via cytokine activation, plays an unclear role in the signaling mechanisms from surgery to molecular activation, and their regulatory effects on inflammation vary. This study aimed to identify key signaling pathways responsible for vascular dysfunction post-surgery and to discover potential targets for predicting or preventing thrombosis. To explore this, endothelial cells were co-cultured with post-surgical trauma serum and analyzed using various assays. Bioinformatics analysis linked surgical trauma with pathways involving thrombosis, interleukins, cytokines, and STAT signaling. Elevated inflammatory mediators were observed in mouse serum post-surgical trauma, with IL-6 activating STAT3 to enhance endothelial proliferation, while IL-1β activated STAT1, inhibiting STAT3′s effects. Gli-similar 2 (GLIS2), a novel coactivator of STAT3, was found to regulate STAT transcription. STAT1, however, inhibited GLIS2′s interaction with STAT3, suppressing STAT3′s role in endothelial proliferation. The study concludes that IL-1β-triggered STAT1 activation impedes GLIS2-STAT3 interaction, reducing STAT3′s transcriptional activity and leading to endothelial dysfunction, presenting new targets for preventing post-surgical trauma endothelial dysfunction and thrombosis.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.