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A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis
Ingo Haase, … , Simon Broad, Fiona M. Watt
Ingo Haase, … , Simon Broad, Fiona M. Watt
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):527-536. https://doi.org/10.1172/JCI12153.
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Article

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

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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.

Authors

Ingo Haase, Robin M. Hobbs, M. Rosario Romero, Simon Broad, Fiona M. Watt

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Figure 1

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Distribution and activation of p42mapk in cultured keratinocytes and in ...
Distribution and activation of p42mapk in cultured keratinocytes and in normal and hyperproliferative human epidermis. Confocal immunofluorescence microscopy of growth factor–starved cultured keratinocytes (a) or keratinocytes treated with FCS + HICE for 15 minutes (b); psoriatic (c, f, and h–j) or normal human epidermis (e and g). Green staining in a–c, e–h, and j is for MAPK with antibody specific for activated (a–c and e) or total MAPK (f–h and j); red staining in h is nuclear dye, Topro III. The field shown in h is part of the field shown in f. (i) Staining for β1 integrins (green) and involucrin (red). Scale bars: 50 μm (a, b, and f–h), 100 μm (c, e, i, and j). (d) Western blot of shaved biopsies of normal human skin (N) or psoriatic lesion (Ps) probed with phosphorylation-specific antibody to ERK1/2 (P-ERK) or total ERK2.

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