Specificity protein 1 is pivotal in the skin’s antiviral response - 10/08/11
, Michael D. Howell, PhD a, b, c, , Byung Eui Kim, MD, PhD a, Joanne E. Streib, BA a, Clifton F. Hall, MS a, Donald Y.M. Leung, MD, PhD a, c, ⁎ 
Reprint requests: Donald Y. M. Leung, MD, PhD, National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206.Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : 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-γ
Abbreviations used : AD, ADEH−, ADEH+, EH, EV, eIF2⍺, GO, HSV-1, KLK, MFI, MOI, NHK, OAS, PKR, siRNA, Sp, VV
Plan
| Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases contracts N01 AI 40029 and N01 AI40033 and NIAMS grant AR41256, and in part by Colorado CTSA grant 1 UL1 RR025780 from NCRR/National Institutes of Health. The salary of L.B. was supported in part by the Eugene F. and Easton M. Crawford Pediatric Research Fellowship Fund at National Jewish Health. |
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| Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 127 - N° 2
P. 430 - février 2011 Retour au numéro
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