Specificity protein 1 is pivotal in the skin's antiviral response

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:127

Article

Bin, Lianghua¹  Howell, Michael D.^1,2,3  Kim, Byung Eui¹  Streib, Joanne E.¹  Hall, Clifton F.¹  Leung, Donald Y. M.^1,3 

[1] Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA

[3] Univ Colorado Denver, Dept Pediat, Aurora, CO USA

关键词: Specificity protein 1;    vaccinia virus;    herpes simplex virus 1;    double-stranded RNA-dependent protein kinase;    2'5'-oligoadenylate synthetase 2;    atopic dermatitis;    eczema herpeticum;    IFN-gamma;   

DOI  :  10.1016/j.jaci.2010.11.013

来源: Elsevier

【 摘 要 】

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-gamma 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-gamma augmentation may be a potential treatment for ADEH(+) patients. (J Allergy Clin Immunol 2011;127:430-8.)

【 授权许可】

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