Activation of eotaxin-3/CCL26 gene expression in human dermal fibroblasts is mediated by STAT6
Activation of eotaxin-3/CCL26 gene expression in human dermal fibroblasts is mediated by STAT6
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DOI：
10.4049/jimmunol.167.6.3216
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发表时间：
2001-09-15
影响因子：
4.4
通讯作者：
Woisetschläger, M
中科院分区：
文献类型：
--
作者：
Hoeck, J;Woisetschläger, M
过敏性炎性病症如哮喘的特征在于嗜酸性粒细胞在炎症部位的积聚。Eotaxin-3/CCL 26是CC趋化因子家族的成员，已知其是嗜酸性粒细胞的有效化学引诱剂。该趋化因子在内皮细胞中被IL-4和IL-13上调。这项研究表明，在人真皮成纤维细胞中，IL-4和IL-13以时间和剂量依赖性方式刺激嗜酸细胞活化趋化因子-3转录和嗜酸细胞活化趋化因子-3蛋白表达。与嗜酸性粒细胞趋化因子-1/CCL11相反，TNF-α本身不能作为诱导剂，也不能与IL-4协同作用。在人皮肤成纤维细胞中，IL-4和IL-13显著增加了嗜酸性粒细胞趋化因子-3启动子荧光素酶构建体的活性。这种效应是由转录因子STAT 6在嗜酸细胞活化趋化因子-3启动子序列中的结合位点介导的。STAT 6结合位点的突变废除了eotaxin-3启动子活性的上调。在STAT 6缺陷的人胚肾293细胞中，野生型荧光素酶构建体，而不是STAT 6结合突变体，仅在共转染STAT 6表达载体后才能被IL-4诱导。此外，在IL-4或IL-13刺激后，在STAT 6转染的人胚肾293细胞的上清液中可检测到嗜酸性粒细胞趋化因子-3蛋白。在相同的实验中，TNF-α诱导的单核细胞趋化蛋白-1/CCL2基因的激活与STAT 6转染无关。这些结果表明IL-4和IL-13以STAT 6依赖性方式激活嗜酸细胞活化趋化因子-3基因表达。尽管嗜酸细胞活化趋化因子-1和-3都受该转录因子调节，但嗜酸细胞活化趋化因子-3基因对TNF-α刺激的反应似乎不同。
Allergic inflammatory conditions such as asthma are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-3/CCL26 is a member of the family of CC chemokines, which are known to be potent chemoattractants for eosinophils. This chemokine was shown to be up-regulated by IL-4 and IL-13 in endothelial cells. This study demonstrates that eotaxin-3 transcription and eotaxin-3 protein expression are stimulated by IL-4 and IL-13 in a time- and dose-dependent fashion in human dermal fibroblasts. In contrast to eotaxin-1/CCL11, TNF-alpha could not act as inducer on its own nor did it synergize with IL-4. The activities of eotaxin-3 promoter luciferase constructs were significantly increased by IL-4 and IL-13 in human dermal fibroblasts. This effect was mediated by a binding site for the transcription factor STAT6 in the eotaxin-3 promoter sequence. Mutations in the STAT6 binding site abrogated up-regulation of eotaxin-3 promoter activity. In STAT6-defective human embryonic kidney 293 cells, the wild-type luciferase construct, but not the STAT6 binding mutant, was inducible by IL-4 only upon cotransfection of STAT6 expression vector. In addition, eotaxin-3 protein was detectable in the supernatants of STAT6-transfected human embryonic kidney 293 cells upon IL-4 or IL-13 stimulation. In the same experiments, TNF-alpha induced activation of the monocyte chemoattractant protein-1/CCL2 gene was independent of STAT6 transfection. These results indicate that IL-4 and IL-13 activate eotaxin-3 gene expression in a STAT6-dependent fashion. Although both eotaxin-1 and -3 are regulated by this transcription factor, the response of the eotaxin-3 gene to TNF-alpha stimulation appears to be different.