Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation
Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation
复制标题
肺上皮中的 Bcl6 协调控制 CC 型趋化因子基因的表达并减轻过敏性气道炎症
DOI：
10.1111/j.1365-2222.2011.03836.x
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发表时间：
2011
期刊：
影响因子：
6.1
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Seto T;et al
研究背景CC-型趋化因子基因簇在人与人之间存在共线性（CCL 2/MCP-1、CCL 7 MCP-3、CCL 11/嗜酸性粒细胞趋化因子、CCL 8/MCP-2、CCL 13/MCP-4和CCL 1/I-309）和小鼠（CCL 2、CCL 7、CCL 11、CCL 12/MCP-5、CCL 8和CCL 1）。由于在簇中观察到许多推定的Bcl 6/STAT结合序列，我们研究了转录抑制因子Bcl 6和区域组蛋白修饰在这些趋化因子基因在肺epithelium.MethodsWe表达的作用产生转基因（Tg）小鼠携带的Bcl 6或显性阴性（DN）-Bcl 6基因的表面活性蛋白C（SPC）的控制下，在远端肺上皮中诱导外源基因表达的启动子。在体外研究中，用IL-4+TNF-α刺激转染SPC-DN-Bcl 6基因的肺泡II型样上皮细胞系A549，并通过染色质免疫沉淀分析Bcl 6或STAT 6与转染子中簇的结合和组蛋白修饰。用卵清蛋白（OVA）致敏的Tg小鼠用OVA吸入激发。结果IL-4和TNF-α刺激A549细胞后，Bcl 6与细胞簇结合的量减少，而STAT 6与区域组蛋白H3-K9/14乙酰化和H3-K4甲基化结合的量增加。基因簇中所有趋化因子基因的表达在转染DN-Bcl 6基因的活化A549细胞中增强。我们还在Tg小鼠中诱导过敏性气道炎症。这些变应性气道炎症的Tg小鼠的肺中的趋化因子基因的表达和浸润的细胞数与肺中Bcl 6的量呈负相关。结论和临床意义肺上皮来源的CC-型趋化因子基因在簇中的表达由Bcl 6相关的保守机制协调。因此，肺上皮细胞中的Bcl 6可能是多种肺部炎症性疾病发病机制的关键调节因子。濑户，M. Yoshitake，T.小笠原，J. Ikari，A.坂本，M。波多野H。Hirata，T.福田，T.栗山湾Tatsumi，T. Tokuhisa和M. Arima，临床与实验过敏，2011（41）1568-1578.
BackgroundThere is synteny in the CC‐type chemokine gene clusters between humans (CCL2/MCP‐1, CCL7MCP‐3, CCL11/eotaxin, CCL8/MCP‐2, CCL13/MCP‐4, and CCL1/I‐309) and mice (CCL2, CCL7, CCL11, CCL12/MCP‐5, CCL8, and CCL1).ObjectiveAs many putative Bcl6/STAT‐binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium.MethodsWe generated transgenic (Tg) mice carrying theBcl6or the dominant‐negative (DN)‐Bcl6gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. Forin vitrostudies, A549, alveolar type II‐like epithelial cell line transfected with theSPC‐DN‐Bcl6gene were stimulated with IL‐4+TNF‐α, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT‐PCR.ResultsThe amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL‐4 and TNF‐α, whereas STAT6 binding increased in association with regional histone H3‐K9/14 acetylation and H3‐K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with theDN‐Bcl6gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs.Conclusion and Clinical RelevanceExpression of the pulmonary epithelium‐derived CC‐type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.Cite this as: T. Seto, M. Yoshitake, T. Ogasawara, J. Ikari, A. Sakamoto, M. Hatano, H. Hirata, T. Fukuda, T. Kuriyama, K. Tatsumi, T. Tokuhisa and M. Arima,Clinical & Experimental Allergy, 2011 (41) 1568–1578.