Department of Dermatology, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Allergy. 2011 Jan;66(1):124-31. doi: 10.1111/j.1398-9995.2010.02440.x.
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.
To elucidate the therapeutic potential of using siRNA to inhibit STAT6 in allergic reactions, we determined the nucleotide sequences of siRNA specific for STAT6.
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-α 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.
Local administration of STAT6 siRNA is thus a promising therapeutic strategy for both Th2-mediated cutaneous diseases and allergic rhinitis.
使用小干扰 RNA（siRNA）沉默基因是一种最近开发的调控靶分子合成的策略。信号转导和转录激活因子 6（STAT6）是一种核转录因子，介导 Th2 型免疫。
为了阐明使用 siRNA 抑制过敏反应中 STAT6 的治疗潜力，我们确定了针对 STAT6 的 siRNA 的核苷酸序列。
所选的 STAT6 siRNA 序列特异性抑制了体外真皮成纤维细胞中 STAT6 合成的产生和白细胞介素-4/肿瘤坏死因子-α诱导的嗜酸性粒细胞趋化因子（CCL11）的产生。体内局部给予 STAT6 siRNA 可减轻对化学半抗原的接触超敏反应。这伴随着局部白细胞介素-4、白细胞介素-13、嗜酸性粒细胞趋化因子（CCL11）、TARC（CCL17）和 MDC（CCL22）的产生减少。同样，连续鼻内给予 STAT6 siRNA 也显著抑制了变应性鼻炎反应中粘膜组织的炎症细胞浸润，同时减少了区域淋巴结细胞产生的白细胞介素-4 和白细胞介素-5。STAT6 siRNA 还改善了打喷嚏和鼻擦等即刻反应。
因此，局部给予 STAT6 siRNA 是一种有前途的 Th2 介导的皮肤疾病和变应性鼻炎的治疗策略。
