Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide
Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide
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DOI：
10.4049/jimmunol.179.4.2556
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Fixman, Elizabeth D.
中科院分区：
文献类型：
--
作者：
McCusker, Christine T.;Wang, Yufa;Fixman, Elizabeth D.
过敏性气道疾病由异常的Th 2炎症反应引发并持续，所述异常的Th 2炎症反应部分地由细胞因子IL-4和IL-13调节，细胞因子IL-4和IL-13中的每一种诱导STAT-6转录因子的活化。来自小鼠模型的数据表明，急性哮喘的临床表现是STAT-6依赖性的，因此，STAT-6是过敏性气道疾病药物开发的靶标。我们设计了一种新的嵌合肽（STAT-6抑制肽（STAT-6-IP）），其由预测结合并抑制STAT-6的序列组成，与蛋白转导结构域融合，以促进STAT-6结合肽的细胞摄取。我们的数据表明STAT-6-IP在体外抑制OVA诱导的Th 2细胞因子IL-4和IL-13的产生。相比之下，STAT-6-IP不影响IFN-γ的产生，证明了对Th 2细胞因子抑制的特异性。鼻内给药后，STAT-6-IP定位于气道上皮细胞。最后，在变应性鼻炎和哮喘的体内鼠模型中，STAT-6-IP的鼻内递送抑制了OVA诱导的肺部炎症和粘液产生以及嗜酸性粒细胞和IL-13在支气管肺泡灌洗液中的积累和OVA依赖性气道高反应性。总之，这些数据表明，局部应用STAT-6的细胞穿透肽抑制剂对于治疗过敏性鼻炎和哮喘具有显著的潜力。
Allergic airways disease is initiated and perpetuated by an aberrant Th2 inflammatory response regulated in part by the cytokines IL-4 and IL-13, each of which induces activation of the STAT-6 transcription factor. Data from murine models indicate that the clinical manifestations of acute asthma are STAT-6 dependent, and thus, STAT-6 is a target for drug development in allergic airways disease. We designed a novel chimeric peptide (STAT-6 inhibitory peptide (STAT-6-IP)) comprised of a sequence predicted to bind to and inhibit STAT-6, fused to a protein transduction domain, to facilitate cellular uptake of the STAT-6-binding peptide. Our data demonstrate that the STAT-6-IP inhibited OVA-induced production of Th2 cytokines IL-4 and IL-13 in vitro. In contrast, the STAT-6-IP did not affect production of IFN-gamma demonstrating specificity for Th2 cytokine inhibition. Following intranasal administration, the STAT-6-IP was localized to epithelial cells in the airways. Finally, in in vivo murine models of allergic rhinitis and asthma, intranasal delivery of the STAT-6-IP inhibited OVA-induced lung inflammation and mucus production as well as accumulation of eosinophils and IL-13 in bronchoalveolar lavage fluid and OVA-dependent airway hyperresponsiveness. Together these data show that local application of cell-penetrating peptide inhibitors of STAT-6 has significant potential for the treatment of allergic rhinitis and asthma.