TGFβ directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes
TGFβ directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes
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DOI：
10.1002/glia.10286
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发表时间：
2003-12-01
期刊：
影响因子：
6.2
通讯作者：
Fontana, A
中科院分区：
文献类型：
--
作者：
Paglinawan, R;Malipiero, U;Fontana, A
在实验性自身免疫性脑脊髓炎中，疾病的急性期由T辅助淋巴细胞1型（T（H）1）产生，其主要产生TNF α和IFN γ。从疾病中恢复是由辅助性T淋巴细胞2型和3型（T（H）2/T（H）3）介导的，其在其他细胞因子中产生转化生长因子β（TGF β）。为了研究TGF β对T（H）1诱导的基因表达的影响，在不存在或存在TGF β的情况下，将微阵列技术用于用IFN γ和TNF α刺激的鼠原代小胶质细胞。从多达5,500个基因的研究中得到的数据提供了这样一种观点，即TGF β阻止了暴露于TH 1环境的小胶质细胞内促炎基因程序的诱导。TH 1细胞因子上调了175个基因，包括细胞因子、趋化因子和参与宿主对感染的反应和TNF α/IFN γ细胞内信号传导途径的基因。观察到TGF β抑制25%的TNF α/IFN γ诱导的基因和另外66个TNF α/IFN γ非依赖性基因的表达。观察到TGF β抑制的焦点指向参与趋化性的基因（IL-15、CXCL 1、CXCL 2、CCL 3、CCL 4、CCL 5、CCL 9），趋化因子受体CCR 5、CCR 9、LIF受体和FPR 2，以及介导细胞迁移的基因（MMP 9、MMP 13、MacMARCKS、内皮素受体B、Ena/VASP、Gas 7）、细胞凋亡（FAS、TNF、TNF受体、半胱天冬酶-1和-11）和宿主对感染的应答（toll样受体6、Mx-1和MARCO）。总的来说，数据强烈表明TGF β的主要作用之一是损害细胞进入中枢神经系统并阻碍小胶质细胞在中枢神经系统实质中的迁移。(C)2003 Wiley-Liss，Inc.
In experimental autoimmune encephalomyelitis, the acute phase of the disease is produced by T-helper lymphocyte type 1 (T(H)1), which produces mainly TNFalpha and IFNgamma. Recovery from the disease is mediated by T-helper lymphocyte types 2 and 3 (T(H)2/T(H)3), which, among other cytokines, produce transforming growth factor beta (TGFbeta). To address the influence of TGFbeta on T(H)1-induced gene expression, microarray technology was used on murine primary microglial cells stimulated with IFNgamma and TNFalpha in the absence or presence of TGFbeta. The resulting data from an investigation of up to 5,500 genes provided the notion that TGFbeta prevents the induction of a proinflammatory gene program within microglia exposed to a TH1 milieu. TH1 cytokines upregulated 175 genes comprising cytokine, chemokine, and genes involved in host response to infection and the TNFalpha/IFNgamma intracellular signaling pathway. It is observed that TGFbeta inhibits expression of 25% of the TNFalpha/IFNgamma-induced genes and a further 66 TNFalpha/IFNgamma-independent genes. The focus of TGFbeta inhibition is observed to be directed in genes involved in chemotaxis (IL-15, CXCL1, CXCL2, CCL3, CCL4, CCL5, CCL9), chemokine receptors (CCR5, CCR9), LIF receptor, and FPR2, and on genes mediating cell migration (MMP9, MMP13, MacMARCKS, endothelin receptor B, Ena/VASP, Gas7), apoptosis (FAS, TNF, TNF receptor, caspase-1 and -11), and host response to infection (toll-like receptor 6, Mx-1, and MARCO). Taken collectively, the data strongly suggest that one of the main effects of TGFbeta is to impair cell entry into the CNS and to hinder migration of microglia in the CNS parenchyma. (C) 2003 Wiley-Liss, Inc.