IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production.
IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production.
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DOI：
10.1038/cmi.2015.02
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发表时间：
2016-03
影响因子：
24.1
通讯作者：
Chung HT
中科院分区：
文献类型：
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作者：
Jamal Uddin M;Joe Y;Kim SK;Oh Jeong S;Ryter SW;Pae HO;Chung HT
免疫应答基因1（IRG1）蛋白在胚胎植入和神经退行性变中具有重要作用。IRG1通过活性氧（ROS）增加巨噬细胞中A20的表达来促进内毒素耐受。产生内源性一氧化碳（CO）的细胞保护蛋白血红素加氧酶-1（HO-1）在脂多糖（LPS）耐受和交叉耐受期间在肺中表达。然而，IRG1和HO-1在先天免疫系统中的详细分子机制和功能联系仍然未知。在本研究中，我们发现CO释放分子-2（CORM-2）和HO-1的化学诱导剂以时间和剂量依赖的方式增加RAW 264.7细胞中IRG1的表达。此外，在这些条件下，通过锌原卟啉IX（ZnPP）和HO-1 siRNA抑制HO-1活性显著降低了IRG1的表达。此外，用CO和HO-1诱导处理显著增加A20表达，这被ZnPP和HO-1 siRNA逆转。应用CORM-2和HO-1诱导LPS刺激的TNF-α显著降低，而IRG1和A20增加，这反过来又被ZnPP消除。有趣的是，针对IRG1和A20的siRNA逆转了CO和HO-1对LPS刺激的TNF-α产生的影响。此外，在LPS刺激的脓毒症小鼠模型中，CO和HO-1诱导剂显著增加IRG1和A20表达，并下调TNF-α的产生。此外，CO和HO-1对TNF-α产生的影响在给予ZnPP时被显著逆转。总之，CO和HO-1诱导调节IRG1和A20表达，导致体外和体内小鼠模型中的炎症抑制。
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.