Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells
Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells
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DOI：
10.1016/j.freeradbiomed.2014.10.579
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发表时间：
2015-01-01
影响因子：
7.4
通讯作者：
Immenschuh, Stephan
中科院分区：
文献类型：
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作者：
Dorresteijn, Mirrin J.;Paine, Ananta;Immenschuh, Stephan
血红素加氧酶（HO）-1是血红素降解酶HO的诱导型异构体，其被多种应激刺激上调。HO-1通过其在单核细胞中的细胞类型特异性功能具有主要的免疫调节和抗炎作用。在这些细胞中，Toll样受体（TLR）4配体脂多糖（LPS）对HO-1的调节有矛盾的发现。因此，我们重新研究了在体外和体内LPS对人和小鼠单核细胞HO-1基因表达的影响。值得注意的是，LPS在原代人外周血单核细胞（PBMC）、CD 14（+）单核细胞、巨噬细胞、树突状细胞和粒细胞中下调HO-1，但在原代鼠巨噬细胞和人单核细胞白血病细胞系中上调该酶。此外，用人CD 14（+）单核细胞进行的实验显示，包括TLR 1、TLR 2、TLR 5、TLR 6、TLR 8和TLR 9在内的其他TLR的激活降低了HO-1 mRNA的表达。HO-1的LPS依赖性下调是特异性的，因为在相同的实验条件下，环氧合酶-2，NADP（H）-醌氧化还原酶-1和peroxiredoxin-1的表达增加。值得注意的是，LPS上调Bach 1的表达，Bach 1是HO-1的关键转录抑制因子。此外，敲低这种核因子增强基础和LPS依赖的HO-1在单核细胞中的表达。最后，在来自经历实验性内毒素血症的人个体的PBMC中证实了响应于LPS的HO-1的下调。总之，LPS通过Bach 1介导的途径下调原代人单核细胞中HO-1的表达。由于LPS依赖的HO-1调节具有细胞类型和物种特异性，因此需要仔细解释细胞系和动物模型中的实验结果。(C)2014爱思唯尔公司All rights reserved.
Heme oxygenase (HO)-1 is the inducible isoform of the heme-degrading enzyme HO, which is upregulated by multiple stress stimuli. HO-1 has major immunomodulatory and anti-inflammatory effects via its cell-type-specific functions in mononuclear cells. Contradictory findings have been reported on HO-1 regulation by the Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) in these cells. Therefore, we reinvestigated the effects of LPS on HO-1 gene expression in human and murine mononuclear cells in vitro and in vivo. Remarkably, LPS downregulated HO-1 in primary human peripheral blood mononuclear cells (PBMCs), CD14(+) monocytes, macrophages, dendritic cells, and granulocytes, but upregulated this enzyme in primary murine macrophages and human monocytic leukemia cell lines. Furthermore, experiments with human CD14(+) monocytes revealed that activation of other TLRs including TLR1, -2, -5, -6, -8, and -9 decreased HO-1 mRNA expression. LPS-dependent downregulation of HO-1 was specific, because expression of cyclooxygenase-2, NADP(H)-quinone oxidoreductase-1, and peroxiredoxin-1 was increased under the same experimental conditions. Notably, LPS upregulated expression of Bach1, a critical transcriptional repressor of HO-1. Moreover, knockdown of this nuclear factor enhanced basal and LPS-dependent HO-1 expression in mononuclear cells. Finally, downregulation of HO-1 in response to LPS was confirmed in PBMCs from human individuals subjected to experimental endotoxemia. In conclusion, LPS downregulates HO-1 expression in primary human mononuclear cells via a Bach1-mediated pathway. As LPS-dependent HO-1 regulation is cell-type- and species-specific, experimental findings in cell lines and animal models need careful interpretation. (C) 2014 Elsevier Inc. All rights reserved.