Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis
Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis
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DOI：
10.1111/j.1398-9995.2010.02440.x
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发表时间：
2011-01-01
期刊：
影响因子：
12.4
通讯作者：
Yokozeki, H.
中科院分区：
文献类型：
--
作者：
Hosoya, K.;Satoh, T.;Yokozeki, H.
背景：利用小干扰RNA（siRNA）沉默基因是近年来发展起来的一种调控靶分子合成的策略。方法：通过对STAT 6特异性siRNA序列的测定，探讨siRNA抑制STAT 6在变态反应中的治疗作用。结果：筛选出的STAT 6 siRNA序列在体外可特异性抑制皮肤成纤维细胞STAT 6的合成及IL-4/TNF-α诱导的嗜酸性粒细胞趋化因子（Eotaxin，CCL 11）的产生。体内局部施用STAT 6 siRNA减轻了对化学半抗原的接触性超敏反应。这伴随着IL-4、IL-13、嗜酸性粒细胞趋化因子（CCL 11）、TARC（CCL 17）和MDC（CCL 22）的局部产生减少。类似地，连续鼻内滴注STAT 6 siRNA显著抑制变应性鼻炎反应中粘膜组织的炎性细胞浸润，这与局部淋巴结细胞产生的IL-4和IL-5减少有关。结论：局部应用STAT 6 siRNA对Th 2介导的皮肤疾病和变应性鼻炎均有较好的治疗效果。
P>Background:Silencing of genes using small interfering RNA (siRNA) is a recently developed strategy to regulate the synthesis of target molecules. Signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity.Methods:To elucidate the therapeutic potential of using siRNA to inhibit STAT6 in allergic reactions, we determined the nucleotide sequences of siRNA specific for STAT6.Results:The selected sequences of STAT6 siRNA specifically inhibited the generation of STAT6 synthesis in dermal fibroblasts and eotaxin (CCL11) production in response to IL-4/TNF-alpha in vitro. Local administration of STAT6 siRNA in vivo alleviated contact hypersensitivity responses to chemical haptens. This was accompanied by reduced local production of IL-4, IL-13, eotaxin (CCL11), TARC (CCL17) and MDC (CCL22). Similarly, consecutive intranasal instillation of STAT6 siRNA markedly inhibited inflammatory cellular infiltration of mucosal tissues in allergic rhinitis responses in association with reduced IL-4 and IL-5 production from regional lymph node cells. Immediate responses, such as sneezing and nasal rubbing behaviors, were also improved by STAT6 siRNA.Conclusions:Local administration of STAT6 siRNA is thus a promising therapeutic strategy for both Th2-mediated cutaneous diseases and allergic rhinitis.