Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2
Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2
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DOI：
10.1189/jlb.0107040
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发表时间：
2008-11-01
影响因子：
5.5
通讯作者：
Ivashkiv, Lionel B.
中科院分区：
文献类型：
--
作者：
Hu, Yang;Park-Min, Kyung-Hyun;Ivashkiv, Lionel B.
TLR配体诱导树突状细胞（DC）成熟，诱导IFN-β表达和对DC功能重要的IFN诱导型Stat 1依赖性基因的自分泌激活。在这项研究中，我们分析了TNF-α和PGE 2在人DC成熟过程中STAT信号的调节，TNF-α和PGE 2诱导LPS刺激的人DC成熟，但不诱导可检测的IFN-β产生或Stat 1酪氨酸磷酸化。与这些结果一致，TNF-α和PGE 2不会诱导Stat 1 DNA与标准Stat 1结合寡核苷酸结合。相反，TNF-α和PGE 2增加了Stat 1丝氨酸磷酸化和Stat 4酪氨酸磷酸化，并激活了NF-κ B和Stat 1靶基因IFN调节因子1（IRF 1）的表达，这有助于IFN应答。TNF-α和PGE 2诱导了一种复合物，该复合物结合了来自IRF 1启动子的寡核苷酸，该启动子含有嵌入较大回文序列中的STAT结合序列，该复合物被Stat 1抗体识别。这些结果表明，TNF-α和PGE 2激活STAT介导的人类DC成熟的组成部分，通过替代途径的IFN-β介导的自分泌环路使用的TLR。J. Leukoc. 84：1353-1360; 2008.
Maturation of dendritic cells (DCs) by TLR ligands induces expression of IFN-beta and autocrine activation of IFN-inducible Stat1-dependent genes important for DC function. In this study, we analyzed the regulation of STAT signaling during maturation of human DCs by TNF-alpha and PGE2, which induced maturation of human DCs comparably with LPS but did not induce detectable IFN-beta production or Stat1 tyrosine phosphorylation. Consistent with these results, TNF-alpha and PGE2 did not induce Stat1 DNA binding to a standard Stat1-binding oligonucleotide. Instead, TNF-alpha and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF-kappa B and Stat1 target gene IFN regulatory factor 1 (IRF1), which contributes to IFN responses. TNF-alpha and PGE2 induced a complex that bound an oligonucleotide derived from the IRF1 promoter that contains a STAT-binding sequence embedded in a larger pal-indromic sequence, and this complex was recognized by Stat1 antibodies. These results suggest that TNF-alpha and PGE2 activate STAT-mediated components of human DC maturation by alternative pathways to the IFN-beta-mediated autocrine loop used by TLRs. J. Leukoc. Biol. 84: 1353-1360; 2008.