The signal transducer and activator of transcription 1α and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide:: Involvement of p38 mitogen-activated protein kinase and nuclear Factor-κB pathways, and synergistic effect of several proinflammatory cytokines
The signal transducer and activator of transcription 1α and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide:: Involvement of p38 mitogen-activated protein kinase and nuclear Factor-κB pathways, and synergistic effect of several proinflammatory cytokines
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DOI：
10.1093/jb/mvj072
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发表时间：
2006-04-01
影响因子：
2.7
通讯作者：
Seishima, Mitsuru
中科院分区：
文献类型：
--
作者：
Fujigaki, Hidetsugu;Saito, Kuniaki;Seishima, Mitsuru
吲哚胺2，3-双加氧酶（IDO）由干扰素（IM-γ）介导的信号转导和转录激活因子1 α（STAT 1 α）和干扰素调节因子（IRF）-1的作用诱导。IDO的诱导也可以通过IFN-γ非依赖性机制介导，尽管诱导机制尚未确定。在这项研究中，我们探讨了脂多糖（LPS）或几种促炎细胞因子是否可以通过IFN-γ非依赖性机制诱导IDO，以及LPS诱导IDO是否需要STAT 1 α和IRF-1信号通路。在外周血单核细胞和THP-1细胞中，LPS或IFN-γ诱导IDO，并且当在肿瘤坏死因子-α、白细胞介素-6或白细胞介素-1 β的组合存在下培养THP-1细胞时，发生协同IDO诱导。使用STAT 1 α和IRF-1共有寡核苷酸探针的电泳迁移率变动测定显示在LPS刺激的THP-1细胞中没有STAT 1 α或IRF-1结合活性。此外，p38促分裂原活化蛋白激酶（MAPK）和核因子-kappa B（NF-kappa B）抑制剂均可抑制LPS诱导的IDO活性。这些结果表明，在THP-1细胞中，LPS诱导IDO不受IFN-γ通过募集STAT 1 α或IRF-1到细胞内信号通路的调节，并且可能与p38 MAPK通路和NF-κ B的活性有关。
Indoleamine 2,3-dioxygenase (IDO) is induced by interferon (IM-gamma-mediated effects of the signal transducer and activator of transcription 1 alpha (STAT1 alpha) and interferon regulatory factor (IRF)-1. The induction of IDO can also be mediated through an IFN-gamma-independent mechanism, although the mechanism of induction has not been identified. In this study, we explored whether lipopolysaccharide (LPS) or several proinflammatory cytokines can induce IDO via an IFN-gamma-independent mechanism, and whether IDO induction by LPS requires the STAT1 alpha and IRF-1 signaling pathways. IDO was induced by LPS or IFN-gamma in peripheral blood mononuclear cells and THP-1 cells, and a synergistic IDO induction occurred when THP-1 cells were cultured in the presence of a combination of tumor necrosis factor-alpha, interleukin-6 or interleukin-1 beta. An electrophoretic mobility shift assay using STAT1 alpha and IRF-1 consensus oligonucleotide probes showed no STAT1 alpha or IRF-1 binding activities in LPS-stimulated THP-1 cells. Further, the LPS-induced IDO activity was inhibited by both p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappa B) inhibitors. These findings suggest that the induction of IDO by LPS in THP-1 cells is not regulated by IFN-gamma via recruitment of STAT1 alpha or IRF-1 to the intracellular signaling pathway, and may be related to the activity of the p38 MAPK pathway and NF-kappa B.