2. Academic Validation
  3. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species

Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species

  • J Biol Chem. 2013 Jun 7;288(23):16225-16234. doi: 10.1074/jbc.M113.454538.
Yingke Li 1,  Peng Zhang 2,  Chengcai Wang 3,  Chaofeng Han 2,  Jun Meng 4,  Xingguang Liu 2,  Sheng Xu 2,  Nan Li 2,  Qingqing Wang 4,  Xueyin Shi 5,  Xuetao Cao 6
Affiliations

Affiliations

  • 1 National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433; Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003.
  • 2 National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
  • 3 Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003.
  • 4 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058.
  • 5 Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003. Electronic address: [email protected].
  • 6 National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100021, China. Electronic address: [email protected].
PMID: 23609450 DOI: 10.1074/jbc.M113.454538
Abstract

Sepsis-associated immunosuppression (SAIS) is regarded as one of main causes for the death of septic patients at the late stage because of the decreased innate immunity with a more opportunistic Infection. LPS-tolerized macrophages, which are re-challenged by LPS after prior exposure to LPS, are regarded as the common model of hypo-responsiveness for SAIS. However, the molecular mechanisms of endotoxin tolerance and SAIS remain to be fully elucidated. In addition, negative regulation of the Toll-like Receptor (TLR)-triggered innate inflammatory response needs further investigation. Here we show that expression of immune responsive gene 1 (IRG1) was highly up-regulated in the peripheral blood mononuclear cells of septic patients and in LPS-tolerized mouse macrophages. IRG1 significantly suppressed TLR-triggered production of proinflammatory cytokines TNF-α, IL-6, and IFN-β in LPS-tolerized macrophages, with the elevated expression of Reactive Oxygen Species (ROS) and A20. Moreover, ROS enhanced A20 expression by increasing the H3K4me3 modification of histone on the A20 promoter domain, and supplement of the ROS abrogated the IRG1 knockdown function in breaking endotoxin tolerance by increasing A20 expression. Our results demonstrate that inducible IRG1 promotes endotoxin tolerance by increasing A20 expression through ROS, indicating a new molecular mechanism regulating hypoinflammation of sepsis and endotoxin tolerance.

Keywords

A20; Endotoxin Tolerance; Immune Responsive Gene 1; Inflammation; Innate Immunity; Macrophages; ROS; Reactive Oxygen Species (ROS); Toll-like Receptors (TLR).

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