title: IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production.
abstract: The immunoresponsive gene 1 (IRG1) 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 IRG1 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-α 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-α production. Additionally, CO and HO-1 inducers significantly increased IRG1 and A20 expression and downregulated TNF-α 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 vitro and in an in vivo mice model.
authors: School of Biological Sciences, University of Ulsan, Korea.
authors: Md
authors: M
authors: Jamal Uddin
authors: School of Biological Sciences, University of Ulsan, Korea.
authors: Yeonsoo
authors: Y
authors: Joe
authors: School of Biological Sciences, University of Ulsan, Korea.
authors: Seul-Ki
authors: SK
authors: Kim
authors: Department of Microbiology and Immunology, Wonkwang University School of Medicine, Korea.
authors: Sun
authors: S
authors: Oh Jeong
authors: Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, USA.
authors: Stefan W
authors: SW
authors: Ryter
authors: Department of Microbiology and Immunology, Wonkwang University School of Medicine, Korea.
authors: Hyun-Ock
authors: HO
authors: Pae
authors: School of Biological Sciences, University of Ulsan, Korea.
authors: Hun Taeg
authors: HT
authors: Chung
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D006836:Hydro-Lyases / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse; D006836:Hydro-Lyases; C487648:Acod1 protein, mouse
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