期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 127, 期 2, 页码 430-U1668出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2010.11.013
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
资金
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [N01 AI 40029, N01 AI40033]
- NIAMS [AR41256]
- NCRR/National Institutes of Health [1 UL1 RR025780]
- National Jewish Health
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.)
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