The cell-specific induction of CXC chemokine ligand 9 mediated by IFN-gamma in microglia of the central nervous system is determined by the myeloid transcription factor PU.1.
The cell-specific induction of CXC chemokine ligand 9 mediated by IFN-gamma in microglia of the central nervous system is determined by the myeloid transcription factor PU.1.
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DOI：
10.4049/jimmunol.1000900
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发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Campbell IL
中科院分区：
文献类型：
--
作者：
Ellis SL;Gysbers V;Manders PM;Li W;Hofer MJ;Müller M;Campbell IL
IFN-γ诱导型趋化因子CXCL 9和CXCL 10参与CNS中T细胞介导的免疫的发病机制。然而，在各种CNS免疫病理中，这些趋化因子的细胞定位与巨噬细胞/小胶质细胞产生的CXCL 9不同，而CXCL 10由巨噬细胞/小胶质细胞和星形胶质细胞产生。在这里，我们确定了IFN-γ诱导的小胶质细胞限制性表达Cxcl 9基因的机制。在培养的神经胶质细胞中，放线菌酮不抑制IFN-γ对CXCL 9（小胶质细胞）和CXCL 10（小胶质细胞和星形胶质细胞）mRNA的诱导。在参与IFN-γ介导的基因调控的各种转录因子中，PU.1被鉴定为在小胶质细胞中组成型表达的核因子，但在星形胶质细胞中不是。STAT 1和PU.1与小胶质细胞中的Cxcl 9基因启动子组成性结合，并且在用IRF-8（鉴定为额外的晚期结合因子）处理IFN-γ后，这显著增加。然而，在星形胶质细胞中，STAT 1单独结合Cxcl 9基因启动子。STAT-1对于IFN-γ诱导小神经胶质细胞中的Cxcl 9和Cxcl 10基因以及小神经胶质细胞和星形胶质细胞中的Cxcl 10基因都是关键的。小胶质细胞中PU.1的siRNA介导的敲低显著损害IFN-γ诱导的CXCL 9，但不损害STAT 1或IRF-8。D1 A星形胶质细胞系的细胞在用PU. 1转导后显示出部分重编程为骨髓样表型，并且除了表达CD 11b之外，还获得了响应IFN-γ产生CXCL 9的能力。因此，PU.1不仅对小胶质细胞中IFN-γ诱导CXCL 9至关重要，而且是这些骨髓细胞特异性表达该趋化因子的关键决定因素。
The IFN-γ-inducible chemokines CXCL9 and CXCL10 are implicated in the pathogenesis of T-cell-mediated immunity in the CNS. However, in various CNS immune pathologies the cellular localization of these chemokines differs with CXCL9 produced by macrophage/microglia while CXCL10 is produced by both macrophage/microglia and astrocytes. Here we determined the mechanism for the microglial cell-restricted expression of the Cxcl9 gene induced by IFN-γ. In cultured glial cells the induction of the CXCL9 (in microglia) and CXCL10 (in microglia and astrocytes) mRNAs by IFN-γ was not inhibited by cycloheximide. Of various transcription factors involved with IFN-γ-mediated gene regulation, PU.1 was identified as a constitutively expressed nuclear factor in microglia but not in astrocytes. STAT1 and PU.1 bound constitutively to the Cxcl9 gene promoter in microglia and this increased significantly following IFN-γ-treatment with IRF-8 identified as an additional late binding factor. However in astrocytes, STAT1 alone bound to the Cxcl9 gene promoter. STAT-1 was critical for IFN-γ-induction of both the Cxcl9 and Cxcl10 genes in microglia and in microglia and astrocytes, respectively. The siRNA-mediated knockdown of PU.1 in microglia markedly impaired IFN-γ-induced CXCL9 but not STAT1 or IRF-8. Cells of the D1A astrocyte line showed partial reprogramming to a myeloid-like phenotype after transduction with PU.1 and, in addition to the expression of CD11b, acquired the ability to produce CXCL9 in response to IFN-γ. Thus, PU.1 not only is crucial for the induction of CXCL9 by IFN-γ in microglia but also is a key determinant factor for the cell-specific expression of this chemokine by these myeloid cells.
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DOI：
10.1084/jem.184.3.963
发表时间：
1996-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Loetscher M;Gerber B;Loetscher P;Jones SA;Piali L;Clark-Lewis I;Baggiolini M;Moser B
通讯作者：
Moser B
影响因子：
2.3
作者：
Kanno, Y;Levi, BZ;Ozato, K
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Ozato, K
影响因子：
5.3
作者：
Kuwata, T;Gongora, C;Ozato, K
通讯作者：
Ozato, K
DOI：
10.1073/pnas.0604800103
发表时间：
2006-12-05
影响因子：
11.1
作者：
Choi, Youn-Hee;Bernardi, Rosa;Benveniste, Etty N.
通讯作者：
Benveniste, Etty N.
DOI：
10.1073/pnas.87.14.5238
发表时间：
1990-07-01
影响因子：
11.1
作者：
FARBER, JM
通讯作者：
FARBER, JM