Cytokine modulation of atopic dermatitis filaggrin skin expression.
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD.


OBJECTIVE
We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response.


METHODS
Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects.


RESULTS
Compared with normal skin, filaggrin expression was significantly reduced (P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 +/- 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 +/- 0.03).


CONCLUSIONS
Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response.


CONCLUSIONS
The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Howell
Michael D
MD
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Kim
Byung Eui
BE
Gao
Peisong
P
Grant
Audrey V
AV
Boguniewicz
Mark
M
Debenedetto
Anna
A
Schneider
Lynda
L
Beck
Lisa A
LA
Barnes
Kathleen C
KC
Leung
Donald Y M
DY
D000328:Adult; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology*; D000091344:Filaggrin Proteins; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000276:immunology*
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018793:Interleukin-13; D007381:Intermediate Filament Proteins; D015847:Interleukin-4