A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis

I. Haase, R. M. Hobbs, M. R. Romero, S. Broad, F. M. Watt

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136 Citations (Scopus)

Abstract

In normal epidermis, β1 integrin expression is confined to the basal layer, whereas in hyperproliferative epidermis, integrins are also expressed in the suprabasal layers. Transgenic mice in which integrins are expressed suprabasally via the involucrin promoter have a sporadic psoriatic phenotype; however, the mechanism by which integrins contribute to the pathogenesis of psoriasis is unknown. We observed activation of mitogen-activated protein kinase (MAPK) in basal and suprabasal keratinocytes of human and transgenic mouse psoriatic lesions and healing mouse skin wounds, correlating in each case with suprabasal integrin expression. Phenotypically normal human and transgenic mouse epidermis did not contain activated MAPK. Transgene-positive keratinocytes produced more IL-1α than controls did, and keratinocyte MAPK could be activated by ligation of suprabasal integrins or treatment with IL-1α. Constitutive activation of MAPK increased the growth rate of human keratinocytes and delayed the onset of terminal differentiation, recreating many of the histological features of psoriatic epidermis. We propose that activation of MAPK by integrins, either directly or through increased IL-1α production, is responsible for epidermal hyperproliferation in psoriasis and wound healing, and that the sporadic phenotype of the transgenic mice may reflect the complex mechanisms by which IL-1 release and responsiveness are controlled in skin.

Original languageEnglish
Pages (from-to)527-536
Number of pages10
JournalJournal of Clinical Investigation
Volume108
Issue number4
DOIs
Publication statusPublished - 2001
Externally publishedYes

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