Psoriatic lesional skin exhibits an aberrant expression pattern of interferon regulatory factor-2 (IRF-2).
Psoriasis is a T-cell-mediated inflammatory skin disease. A Th1 cytokine profile with increased levels of interferon-gamma (IFN-gamma) is predominant in skin and peripheral blood mononuclear cells (PBMCs) from psoriasis patients. Furthermore, psoriatic keratinocytes exhibit an aberrant sensitivity and response to IFN-gamma. The transcriptional activator interferon regulatory factor-1 (IRF-1) plays a crucial role in the activation of IFN-gamma-induced gene expression. Recently it was shown that mice deficient in IRF-2, a transcriptional repressor of IFN signalling and thereby acting as an IRF-1 antagonist, display psoriasis-like skin abnormalities. It was therefore hypothesized that a dysbalance between IRF-1 and IRF-2, the activator and repressor of IFN responses, respectively, contributes to the altered IFN-gamma signalling observed in patients with psoriasis. In the epidermis of patients with psoriasis and healthy controls, similar IRF-1 and IRF-2 mRNA expression levels were observed. Furthermore, it was not possible to detect any differences in IRF-1 and IRF-2 protein levels in nuclear extracts from the epidermis of controls and psoriasis patients by electrophoretic mobility shift assay and western blot analysis. Using double immunofluorescence labelling, it was observed that in normal skin IRF-1 was expressed in keratinocytes throughout the epidermis, whereas IRF-2 was restricted to the basal cell layer. In psoriatic skin, IRF-1 expression was comparable to normal skin, whereas IRF-2 was expressed in both basal and suprabasal cell layers. This altered IRF-2 expression in suprabasal cell layers may therefore result in a dysbalance between the activator and repressor of IFN responses in these cell layers, putatively contributing to aberrant responses to IFN-gamma and eventually to the psoriatic skin phenotype.
van der Fits
Leslie
L
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. vanderfits@immu.fgg.eur.nl
van der Wel
Leontine I
LI
Laman
Jon D
JD
Prens
Errol P
EP
Verschuren
Martie C M
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western / Q000379:methods; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012867:Skin / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma