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p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome

Author

Listed:
  • Jianming Wang

    (Rutgers University)

  • Chun-Yuan Chang

    (Rutgers University)

  • Xue Yang

    (Rutgers University)

  • Fan Zhou

    (Rutgers University)

  • Juan Liu

    (Rutgers University)

  • Jill Bargonetti

    (Hunter College, City University of New York)

  • Lanjing Zhang

    (Rutgers University
    Rutgers University
    Penn Medicine Princeton Medical Center)

  • Ping Xie

    (Rutgers University
    Rutgers University)

  • Zhaohui Feng

    (Rutgers University)

  • Wenwei Hu

    (Rutgers University)

Abstract

Radiation-induced gastrointestinal syndrome is a major complication and limiting factor for radiotherapy. Tumor suppressor p53 has a protective role in radiation-induced gastrointestinal toxicity. However, its underlying mechanism remains unclear. Here we report that regulating the IL12-p40/MHC class II signaling pathway is a critical mechanism by which p53 protects against radiation-induced gastrointestinal syndrome. p53 inhibits the expression of inflammatory cytokine IL12-p40, which in turn suppresses the expression of MHC class II on intestinal epithelial cells to suppress T cell activation and inflammation post-irradiation that causes intestinal stem cell damage. Anti-IL12-p40 neutralizing antibody inhibits inflammation and rescues the defects in intestinal epithelial regeneration post-irradiation in p53-deficient mice and prolongs mouse survival. These results uncover that the IL12-p40/MHC class II signaling mediates the essential role of p53 in ensuring intestinal stem cell function and proper immune reaction in response to radiation to protect mucosal epithelium, and suggest a potential therapeutic strategy to protect against radiation-induced gastrointestinal syndrome.

Suggested Citation

  • Jianming Wang & Chun-Yuan Chang & Xue Yang & Fan Zhou & Juan Liu & Jill Bargonetti & Lanjing Zhang & Ping Xie & Zhaohui Feng & Wenwei Hu, 2024. "p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44390-w
    DOI: 10.1038/s41467-023-44390-w
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    as
    1. Chun-Yuan Chang & Jianming Wang & Yuhan Zhao & Juan Liu & Xue Yang & Xuetian Yue & Huaying Wang & Fan Zhou & Juan M. Inclan-Rico & John J. Ponessa & Ping Xie & Lanjing Zhang & Mark C. Siracusa & Zhaoh, 2021. "Tumor suppressor p53 regulates intestinal type 2 immunity," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Eliran Kadosh & Irit Snir-Alkalay & Avanthika Venkatachalam & Shahaf May & Audrey Lasry & Ela Elyada & Adar Zinger & Maya Shaham & Gitit Vaalani & Marco Mernberger & Thorsten Stiewe & Eli Pikarsky & M, 2020. "The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic," Nature, Nature, vol. 586(7827), pages 133-138, October.
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