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Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis - Zurich Open Repository and Archive


Rebane, Ana; Zimmermann, Maya; Aab, Alar; Baurecht, Hansjörg; Koreck, Andrea; Karelson, Maire; Abram, Kristi; Metsalu, Tauno; Pihlap, Maire; Meyer, Norbert; Fölster-Holst, Regina; Nagy, Nikoletta; Kemeny, Lajos; Kingo, Külli; Vilo, Jaak; Illig, Thomas; Akdis, Mübeccel; Franke, Andre; Novak, Natalija; Weidinger, Stephan; Akdis, Cezmi A (2012). Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 129(5):1297-1306.

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.

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.

Citations

52 citations in Web of Science®
59 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Swiss Institute of Allergy and Asthma Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:23 March 2012
Deposited On:04 Jun 2012 07:14
Last Modified:14 Mar 2017 08:12
Publisher:Elsevier
ISSN:0091-6749
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jaci.2012.02.020
PubMed ID:22445417

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