Nuclear factor-κB activation in airway epithelium induces inflammation and hyperresponsiveness
Nuclear factor-κB activation in airway epithelium induces inflammation and hyperresponsiveness
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DOI：
10.1164/rccm.200707-1096oc
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发表时间：
2008-05-01
影响因子：
24.7
通讯作者：
Janssen-Heininger, Yvonne M. W.
中科院分区：
文献类型：
--
作者：
Pantano, Cristen;Ather, Jennifer L.;Janssen-Heininger, Yvonne M. W.
理由：核因子(NF)- κ B是一种重要的促炎转录因子，在变应性气道疾病中起关键作用。先前的研究表明，抑制气道上皮nf - κ B可导致变应性炎症的衰减。目的：我们试图确定在没有其他激动剂的情况下，气道上皮内NF-kappa B的选择性激活是否足以引起过敏性气道疾病。方法：在大鼠CC10启动子的转录控制下，制备了表达多西环素（Dox）诱导的、组成活性（CA）版kappa B （I kappa B）激酶β (IKK β)抑制剂的转基因小鼠。测量和主要结果：给药Dox后，CA-IKK β基因表达诱导气道上皮ReIA核易位。IKK β触发的NF-kappa B激活导致中性粒细胞和淋巴细胞含量增加，并伴随促炎介质的产生，这些反应在未接受Dox的转基因小鼠或饲喂Dox的转基因阴性对照动物中未观察到。出乎意料的是，在没有抗原致敏和刺激方案、嗜酸性粒细胞存在或诱导粘液化生的情况下，IKK β转基因在气道上皮中的表达足以引起气道高反应性和平滑肌增厚。结论：气道上皮NF-kappa B的选择性激活足以诱导气道高反应性和平滑肌增厚，这两者都是变应性气道疾病的重要特征。
Rationale: Nuclear factor (NF)-kappa B is a prominent proinflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of NF-kappa B in airway epithelium causes attenuation of allergic inflammation.Objectives: We sought to determine if selective activation of NF-kappa B within the airway epithelium in the absence of other agonists is sufficient to cause allergic airway disease.Methods: A transgenic mouse expressing a doxycycline (Dox)-inducible, constitutively active (CA) version of inhibitor of kappa B (I kappa B) kinase-beta (IKK beta) under transcriptional control of the rat CC10 promoter, was generated.Measurements and Main Results: After administration of Dox, expression of the CA-IKK beta transgene induced the nuclear translocation of ReIA in airway epithelium. IKK beta-triggered activation of NF-kappa B led to an increased content of neutrophils and lymphocytes, and concomitant production of proinflammatory mediators, responses that were not observed in transgenic mice not receiving Dox, or in transgene-negative littermate control animals fed Dox. Unexpectedly, expression of the IKK beta transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia.Conclusions: These findings demonstrate that selective activation NF-kappa B in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.