Airway epithelial NF-κB activation promotes the ability to overcome inhalational antigen tolerance.
Airway epithelial NF-κB activation promotes the ability to overcome inhalational antigen tolerance.
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DOI：
10.1111/cea.12491
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Poynter ME
中科院分区：
文献类型：
--
作者：
Ather JL;Foley KL;Suratt BT;Boyson JE;Poynter ME
吸入性抗原耐受通常可防止过敏性气道疾病的发展，但可被克服以在哮喘发展之前诱导过敏性致敏。我们在体内研究了是否可以通过激活传导气道上皮细胞中的转录因子NF-κB来克服预先存在的吸入性抗原耐受，并使用体内和体外方法相结合来研究所涉及的机制。能够在气道上皮中表达组成型活性IκB激酶β（CAIKKβ）的野生型和转基因小鼠对吸入的卵白蛋白耐受。28天后，瞬时表达转基因，并在第30天将小鼠暴露于吸入的OVA，以试图克服吸入耐受性。在第40-42天卵清蛋白激发后，转基因已被激活的CAIKKβ小鼠表现出过敏性气道疾病的特征，包括气道嗜酸性粒细胞增多和乙酰甲胆碱高反应性。在第31天，CAIKKβ小鼠中存在CD 103+和CD 11bHI肺树突状细胞群的增加。表达CAIKKβ小鼠的支气管肺泡灌洗诱导CD 4 + T细胞分泌TH 2和TH 17细胞因子，这一效应分别需要IL-4和IL-1信号传导。服用Dox的CAIKKβ小鼠表现出肺部先天淋巴2型细胞（ILC 2）数量增加，并且TH 2极化细胞因子IL-4的mRNA表达也升高。最后，气道上皮NF-kB激活诱导CAIKKβ小鼠对Dox的过敏性致敏，这需要体内IL-4和IL-1信号传导。我们的研究表明，气道上皮细胞NF-κB激活后产生的可溶性介质通过可溶性介质（包括IL-1和IL-4）对肺树突状细胞以及先天性淋巴和CD 4 + T细胞的作用，协调了吸入耐受和过敏性抗原致敏的破坏。
Inhalational antigen tolerance typically protects against the development of allergic airway disease but may be overcome to induce allergic sensitization preceding the development of asthma. We examined in vivo whether pre-existing inhalational antigen tolerance could be overcome by activation of the transcription factor NF-κB in conducting airway epithelial cells, and used a combination of in vivo and in vitro approaches to examine the mechanisms involved. Wildtype and transgenic mice capable of expressing constitutively active IκB kinase β (CAIKKβ) in airway epithelium were tolerized to inhaled ovalbumin. Twenty-eight days later, the transgene was transiently expressed and mice were exposed to inhaled OVA on day 30 in an attempt to overcome inhalational tolerance. Following ovalbumin challenge on days 40-42, CAIKKβ mice in which the transgene had been activated exhibited characteristic features of allergic airway disease, including airway eosinophilia and methacholine hyperresponsiveness. Increases in the CD103+ and CD11bHI lung dendritic cell populations were present in CAIKKβ mice on day 31. Bronchoalveolar lavage from mice expressing CAIKKβ mice induced CD4+ T cells to secrete TH2 and TH17 cytokines, an effect that required IL-4 and IL-1 signaling, respectively. CAIKKβ mice on Dox demonstrated increased numbers of innate lymphoid type 2 cells (ILC2) in the lung, which also exhibited elevated mRNA expression of the TH2-polarizing cytokine IL-4. Finally, airway epithelial NF-kB activation induced allergic sensitization in CAIKKβ mice on Dox that required IL-4 and IL-1-signaling in vivo. Our studies demonstrate that soluble mediators generated in response to airway epithelial NF-κB activation orchestrate the breaking of inhalational tolerance and allergic antigen sensitization through the effects of soluble mediators, including IL-1 and IL-4, on pulmonary dendritic cells as well as innate lymphoid and CD4+ T cells.
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DOI：
10.1073/pnas.0902745106
发表时间：
2009-04-28
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Ruedl, Christiane
影响因子：
15.9
作者：
Ostroukhova, M;Seguin-Devaux, C;Ray, A
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