Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages
Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages
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DOI：
10.1016/j.molimm.2007.10.011
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Yoshida, Takemi
中科院分区：
文献类型：
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作者：
Ashino, Takashi;Yamanaka, Rieko;Yoshida, Takemi
血红素氧合酶-1（HO-1）在感染性疾病下在巨噬细胞中被诱导。我们使用各种基因缺陷小鼠衍生的巨噬细胞进行实验，以确定脂多糖（LPS）诱导HO-1的详细机制以及HO-1诱导巨噬细胞的功能作用。处理后6小时和12小时，LPS（1 μ g/mL）分别最大限度地诱导野生型（WT）巨噬细胞中的诱导型一氧化氮合酶（iNOS）和HO-1 mRNA，并从WT巨噬细胞中释放肿瘤坏死因子α（TNF α）。LPS还诱导TNF α（-/-）巨噬细胞中的iNOS和HO-1，但不诱导iNOS（-/-）巨噬细胞。有趣的是，虽然LPS强烈诱导iNOS，但在核因子红细胞2相关因子2（Nrf 2）（-/-）巨噬细胞中几乎不能完全诱导HO-1。HO-1诱导剂hemin和Co-原卟啉（CoPP）预处理可抑制LPS诱导的WT巨噬细胞iNOS基因表达，而HO-1抑制剂Sn-原卟啉对LPS诱导的WT巨噬细胞iNOS基因表达无影响。在Nrf 2（-/-）巨噬细胞中，CoPP诱导HO-1的能力及其对LPS诱导的iNOS基因表达的抑制作用低于WT巨噬细胞。目前的研究结果表明，HO-1是通过诱导NO诱导的Nrf 2的核转位，HO-1的酶功能抑制NO在巨噬细胞中的过量产生。(C)2007爱思唯尔有限公司保留所有权利。
Heme oxygenase-1 (HO-1) is induced under infectious diseases in macrophages. We performed experiments using various gene deficient mouse-derived macrophages to determine a detailed induction mechanism of HO-1 by lipopolysaccharide, (LPS) and the functional role of HO-1 induction in macrophages. LPS (1 mu g/mL) maximally induced inducible nitric oxide synthase (iNOS) and HO-1 mRNAs in wild-type (WT) macrophages at 6 h and 12 h after treatment, respectively, and liberated tumor necrosis factor alpha (TNF alpha) from WT macrophages. LPS also induced iNOS and HO-1 in TNF alpha(-/-) macrophages, but not in iNOS(-/-) macrophages. Interestingly, although LPS strongly induced iNOS, it failed to induce HO-1 almost completely in nuclear-factor erythroid 2-related factor 2 (Nrf2)(-/-) macrophages. The LPS-induced iNOS gene expression was suppressed by pretreatment with HO-1 inducers, hemin and Co-protoporphyrin (CoPP), but not with HO-1 inhibitor, Sn-protoporphyrin in WT macrophages. In the Nrf2(-/-) macrophages, the ability of CoPP to induce HO-1 and its inhibitory effect on the LPS-induced iNOS gene expression were lower than seen in WT macrophages. The present findings suggest that HO-1 is induced via NO-induced nuclear translocation of Nrf2, and the enzymatic function of HO-1 inhibits the overproduction of NO in macrophages. (C) 2007 Elsevier Ltd. All rights reserved.