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Psoriatic keratinocytes show reduced IRF-1 and STAT-1 activation in response to -IFN

Departments of

^a Dermatology and

^b Pathology, University of Edinburgh, Edinburgh EH3 9YW, Scotland, U.K.

Psoriasis is a chronic inflammatory dermatosis characterized by hyperproliferative keratinocytes (KC). The skin lesions are infiltrated by T cells, which secrete gamma interferon (-IFN) and are believed to be necessary to maintain the psoriatic phenotype. In normal KC, -IFN is a potent inhibitor of proliferation, but proliferation of KC persists in psoriatic plaques despite the presence of -IFN. Immunostaining of interferon regulatory factor-1 (IRF-1) revealed that IRF-1 was localized to the basal cells of the epidermis in normal and in nonlesional psoriatic skin, but was suprabasal or completely absent in lesional psoriatic skin. This finding led to the hypothesis that abnormal signaling in the -IFN pathway may occur in psoriatic KC. To test this hypothesis, we measured activation of IRF-1 and signal transducer and activator of transcription (STAT)-1 transcription factors in KC after stimulation with -IFN. Primary cultures of KC from normal and nonlesional psoriatic skin were stimulated with -IFN and subsequent transcription factor activation was measured by electrophoretic mobility shift assay. Psoriatic KC showed a reduced induction of IRF-1 and STAT-1 activation after stimulation with -IFN, compared with normal KC. Reduced activation of IRF-1 and STAT-1 in response to -IFN indicates a fundamental defect in the growth and differentiation control of psoriatic KC in the absence of the influence of other cell types.—Jackson, M., Howie, S. E. M., Weller, R., Sabin, E., Hunter, J. A. A., McKenzie, R. C. Psoriatic keratinocytes show reduced IRF-1 and STAT 1- activation in response to -IFN.

¹ Correspondence: Department of Dermatology, University of Edinburgh, Lauriston Bldg. RIE, EH3 9YW, Scotland, U.K. E-mail: Roddie.McKenzie{at}ed.ac.uk

Key Words: psoriasis • -interferon • fibronectin • KC • GAS sites

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