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

J Allergy Clin Immunol. 2012 May;129(5):1297-306. doi: 10.1016/j.jaci.2012.02.020. Epub 2012 Mar 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / genetics
  • Adrenomedullin / immunology
  • Adrenomedullin / metabolism
  • Aged
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / metabolism
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Biopsy
  • Cells, Cultured
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / immunology
  • Chemokine CCL5 / metabolism
  • Chemokine CCL8 / genetics
  • Chemokine CCL8 / immunology
  • Chemokine CCL8 / metabolism
  • Computational Biology
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / immunology*
  • Dermatitis, Atopic / metabolism
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / immunology
  • Dual Specificity Phosphatase 1 / metabolism
  • Female
  • Gene Expression Profiling
  • Genetic Markers / genetics
  • Genome-Wide Association Study
  • Humans
  • Interferon-gamma / immunology*
  • Interferon-gamma / pharmacology
  • Keratinocytes / drug effects
  • Keratinocytes / immunology*
  • Keratinocytes / pathology
  • Male
  • Middle Aged
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / immunology
  • Nod2 Signaling Adaptor Protein / metabolism
  • Polymorphism, Single Nucleotide
  • Skin / pathology*
  • Up-Regulation / immunology


  • ADM protein, human
  • Antigens, Differentiation
  • Chemokine CCL5
  • Chemokine CCL8
  • Genetic Markers
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • leu-13 antigen
  • Adrenomedullin
  • Interferon-gamma
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1