特异性蛋白 1 在皮肤的抗病毒反应中起着关键作用。
Specificity protein 1 is pivotal in the skin's antiviral response.
机构信息
Department of Pediatrics, National Jewish Health, Denver, Colo, USA.
出版信息
J Allergy Clin Immunol. 2011 Feb;127(2):430-438.e1-2. doi: 10.1016/j.jaci.2010.11.013. Epub 2011 Jan 5.
BACKGROUND
Previous studies have found specificity protein (Sp) 1 transcription factor in the viral replication machinery and postulated that Sp1 was required for viral replication in host cells.
OBJECTIVES
We investigated the role of Sp1 in the skin's antiviral responses from the perspective of host defense and its biological relevance in patients with atopic dermatitis and a history of eczema herpeticum (ADEH(+)).
METHODS
Small interfering RNA duplexes were used to knock down Sp1 in keratinocytes. The expression of vaccinia virus (VV), herpes simplex virus 1, and other genes were evaluated by real-time PCR, or combined with Western blot and immunohistofluorescence staining. A total of 106 human subjects participated in this study.
RESULTS
Both VV and herpes simplex virus 1 replication were enhanced in Sp1 knocked-down keratinocytes. Sp1 gene expression was significantly decreased in ADEH(+) subjects compared with patients with atopic dermatitis without a history of eczema herpeticum and nonatopic subjects (P < .0001) and inversely correlated with VV DNA copy number in human skin explants incubated with VV in vitro (partial correlation r = -0.256; P = .009). Gene profiling revealed that the antiviral genes, double-stranded RNA-dependent protein kinase (PKR) and 2'5'-oligoadenylate synthetase 2 (OAS2), were significantly downregulated in Sp1-silenced keratinocytes. Gene expression of PKR and OAS2 was also significantly decreased in skin biopsies from ADEH(+) subjects compared with patients with atopic dermatitis without a history of eczema herpeticum and nonatopic subjects. IFN-γ augmented the antiviral capacity of Sp1-silenced keratinocytes.
CONCLUSION
Specificity protein 1 knockdown enhances viral replication in keratinocytes by downregulating gene expression of PKR and OAS2. Sp1 deficiency in ADEH(+) patients may contribute to their increased propensity to disseminated skin viral infections. IFN-γ augmentation may be a potential treatment for ADEH(+) patients.
背景
先前的研究发现特异性蛋白（Sp）1 转录因子存在于病毒复制机制中，并推测 Sp1 是病毒在宿主细胞中复制所必需的。
目的
我们从宿主防御的角度研究了 Sp1 在皮肤抗病毒反应中的作用及其在特应性皮炎和疱疹性湿疹病史（ADEH(+)）患者中的生物学相关性。
方法
使用小干扰 RNA 双链体敲低角质形成细胞中的 Sp1。通过实时 PCR 评估牛痘病毒（VV）、单纯疱疹病毒 1 和其他基因的表达，或结合 Western blot 和免疫荧光染色。共有 106 名受试者参与了这项研究。
结果
VV 和单纯疱疹病毒 1 的复制在 Sp1 敲低的角质形成细胞中均增强。与无疱疹性湿疹病史的特应性皮炎患者和非特应性受试者相比，ADEH(+) 受试者的 Sp1 基因表达显著降低（P <.0001），并且与体外孵育 VV 的人皮肤外植体中的 VV DNA 拷贝数呈负相关（部分相关 r = -0.256；P =.009）。基因谱分析显示，抗病毒基因双链 RNA 依赖性蛋白激酶（PKR）和 2'5'-寡腺苷酸合成酶 2（OAS2）在 Sp1 沉默的角质形成细胞中显著下调。与无疱疹性湿疹病史的特应性皮炎患者和非特应性受试者相比，ADEH(+) 受试者的皮肤活检中 PKR 和 OAS2 的基因表达也显著降低。IFN-γ 增强了 Sp1 沉默角质形成细胞的抗病毒能力。
结论
Sp1 敲低通过下调 PKR 和 OAS2 的基因表达增强角质形成细胞中的病毒复制。ADEH(+) 患者 Sp1 缺乏可能导致其皮肤病毒感染扩散的易感性增加。IFN-γ 增强可能是 ADEH(+) 患者的一种潜在治疗方法。
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