Mechanisms of IFN-纬-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis

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• 作者：Ana Rebane ; PhD^a ; ^b ; ^&lowast ; ; ^{ana.rebane@siaf.uzh.ch} ; Maya Zimmermann ; PhD^a ; ^&lowast ; ; Alar Aab ; MSc^a ; Hansjö ; rg 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 Fö ; lster-Holst ; MD^c ; Nikoletta Nagy ; MD ; PhD^d ; ^g ; Lajos Kemeny ; MD^d ; ^g ; Kü ; lli Kingo ; MD ; PhD^e ; ^h ; Jaak Vilo ; PhD^f ; Thomas Illig ; MDⁱ ; ^j ; Mü ; beccel Akdis ; MD ; PhD^a ; Andre Franke ; PhD^k ; Natalija Novak ; MD^l ; Stephan Weidinger ; MD^c ; Cezmi A. Akdis ; MD^a
• 关键词：Cytokine ; mRNA expression array ; atopic eczema ; inflammation ; allergy
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 期刊代码：158_00916749
• 类别：med
• 出版时间：May, 2012
• 卷：129
• 期：5
• 页码：1297-1306
• 文件大小：1309 K

摘要

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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-纬-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-纬 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-纬 responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD.