Inhibition of S100A11 gene expression impairs keratinocyte response against vaccinia virus through downregulation of the IL-10 receptor 2 chain - 20/08/11
Reprint requests: Donald Y. M. Leung, MD, PhD, National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206.Abstract |
Background |
The mechanism that predisposes patients with atopic dermatitis (AD) to disseminated vaccinia viral (VV) skin infection after smallpox vaccination is unknown. We have demonstrated that expression of S100A11, a calcium-binding protein involved in keratinocyte differentiation, is downregulated in AD.
Objective |
We investigated whether inhibiting expression of S100A11 increased VV replication in human keratinocytes and the mechanism by which S100A11 affects the innate immune response of keratinocytes.
Methods |
Small interfering RNA duplexes were used to reduce gene expression of S100A11 in keratinocytes. VV replication was evaluated by real-time PCR and viral plaque assay. VV cytopathic effect was assessed by crystal violet staining. Affymetrix GeneChip assay was used to compare gene expression profiles. Real time PCR, Western blotting, and immunohistochemistry staining assay were used to evaluate gene expression in keratinocytes and AD skin biopsies.
Results |
Keratinocytes with deficient S100A11 expression supported increased VV replication and manifested augmented VV cytopathic effects. Gene microarray analysis revealed that the IL-10 receptor 2 chain (IL-10R2), which binds IFN-λs, was downregulated by 2.26-fold in S100A11-silenced keratinocytes. IL-10R2 expression was found to be decreased in skin biopsies from patients with acute AD (mean, 25.21 ± 5.25; n = 20) compared with skin from normal healthy subjects (mean, 137.1 ± 34.46; n = 19; P < .01). Furthermore, deficient S100A11 gene expression significantly impaired IL-29 (IFN-λ1) responsiveness (2′ 5′-oligoadenylate synthetase and Myxovirus [influenza virus] resistance induction) and its anti-VV effects in keratinocytes.
Conclusions |
Inhibition of S100A11 gene expression impairs the ability of keratinocytes to control VV replication via downregulation of IFN-λ receptor IL-10R2.
Le texte complet de cet article est disponible en PDF.Key words : S100A11, atopic dermatitis, vaccinia virus, IL-10 receptor, IFN-λ, IL-29
Abbreviations used : AD, GAPDH, IL-10R2, MOI, NHK, OAS, siRNA, VV
Plan
| Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases contracts N01 AI 40029, N01 AI40030, and AR41256. Dr. Bin’s salary 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 124 - N° 2
P. 270 - août 2009 Retour au numéro
Article précédent
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