IRG1 induced by heme oxygenase- 1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production

• Published in: Cellular & molecular immunology 2016-03, Vol.13 (2), p.170-179
• Main Authors: Jamal Uddin, Md, Joe, Yeonsoo, Kim, Seul-Ki, Oh Jeong, Sun, Ryter, Stefan W, Pae, Hyun-Ock, Chung, Hun Taeg
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Carbon Monoxide - pharmacology; Cell Line; Gene Expression Regulation - drug effects; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - immunology; Hydro-Lyases - immunology; Immunology; Lipopolysaccharides - toxicity; LPS; Male; Medical Microbiology; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - immunology; Mice; Microbiology; RAW264.7细胞; research-article; Sepsis - chemically induced; Sepsis - immunology; Sepsis - pathology; Tumor Necrosis Factor alpha-Induced Protein 3 - immunology; Tumor Necrosis Factor-alpha - immunology; Vaccine; 内源性一氧化碳; 化学诱导; 炎性细胞因子; 生产; 脓毒症; 血红素加氧酶
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2015.02

The immunoresponsive gene 1 （IRG 1） protein has crucial functions in embryonic implantation and neurodegeneration. IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species （ROS）. The cytoprotective protein heme oxygenase-1 （HO-1）, which generates endogenous carbon monoxide （CO）, is expressed in the lung during Lipopolysaccharide （LPS） tolerance and cross tolerance. However, the detailed molecular mechanisms and functional links between IRG1 and HO-1 in the innate immune system remain unknown. In the present study, we found that the CO releasing molecule-2 （CORM-2） and chemical inducers of HO- 1 increased I RG 1 expression in a time- and dose-dependent fashion in RAW264.7 cells. Furthermore, inhibition of HO-1 activity by zinc protoporphyrin IX （ZnPP） and HO-1 siRNA significantly reduced expression of IRG1 under these conditions. In addition, treatment with CO and HO-1 induction significantly increased A20 expression, which was reversed by ZnPP and HO-1 siRNA. LPS-stimulated TNF-a was significantly decreased, whereas IRG1 and A20 were increased by CORM-2 application and HO-1 induction, which in turn were abrogated by ZnPP. Interestingly, siRNA against IRG1 and A20 reversed the effects of CO and HO-1 on LPS-stimulated TNF-a production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-a production in a LPS-stimulated sepsis mice model. Furthermore, the effects of CO and HO-1 on TNF-α production were significantly reversed when ZnPP was administered. In conclusion, CO and HO-1 induction regulates IRG1 and A20 expression, leading to inhibition of inflammation in vitroand in an in vivomice model.