Mechanisms of IFN-γ–induced apoptosis of human skin keratinocytes in patients with atopic dermatitis - 28/04/12
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, Maya Zimmermann, PhD a, , Alar Aab, MSc a, Hansjörg Baurecht, MSc c, Andrea Koreck, MD d, Maire Karelson, MD e, Kristi Abram, MD e, Tauno Metsalu, MSc f, Maire Pihlap, BSc b, Norbert Meyer, MD a, Regina Fölster-Holst, MD c, Nikoletta Nagy, MD, PhD d, g, Lajos Kemeny, MD d, g, Külli Kingo, MD, PhD e, h, Jaak Vilo, PhD f, Thomas Illig, MD i, j, Mübeccel Akdis, MD, PhD a, Andre Franke, PhD k, Natalija Novak, MD l, Stephan Weidinger, MD c, Cezmi A. Akdis, MD aCorresponding author: Ana Rebane, PhD, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, 7270 Davos, Switzerland.Abstract |
Background |
Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD).
Objective |
The aim of the study was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes.
Methods |
Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data.
Results |
We demonstrate that keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system–related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31, DUSP1, and ADM genes.
Conclusion |
Our results demonstrate increased IFN-γ responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD.
Le texte complet de cet article est disponible en PDF.Key words : Cytokine, mRNA expression array, atopic eczema, inflammation, allergy
Abbreviations used : 7-AAD, AD, FAS, FN14, KORA, qRT-PCR, SNP, TNF-R, TRAIL, TWEAK
Plan
| Supported by Swiss National Science Foundation grants 32-132899 and 32-112306, the Christine Kühne Center for Allergy Research and Education (CK-CARE), Estonian Ministry of Education and Research targeted funds SF0180021s07 and SF0180043s07, and Estonian Science Foundation grants ESF8350 and ETF7437. A.R. was supported by fellowships from the SCIEX Programme NMS-CH and ESTBIOREG. S.W. is supported by a Heisenberg professorship of the DFG (WE2678/4-1). |
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| Disclosure of potential conflict of interest: M. Akdis receives research support from the Swiss National Foundation and the European Union. N. Novak has received research support from the German Research Council; has received lecture fees from Astellas and ALK-Abelló; and is on an advisory board for LEO Pharma. C. A. Akdis has received research support from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, the Global Allergy and Asthma European Network, and the Christine Kühne Center for Allergy Research and Education and has consulted for Actellion, Aventis, Stallergenes, and Allergopharma. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 129 - N° 5
P. 1297-1306 - mai 2012 Retour au numéro
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