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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 3

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Integrin-mediated MAPK phosphorylation. Western blot analysis of MAPK ph...
Integrin-mediated MAPK phosphorylation. Western blot analysis of MAPK phosphorylation: upper panels show threonine/tyrosine phosphorylation of ERK1/2 visualized with a phosphorylation-specific antibody; lower panels show the same blots incubated with an antibody against total ERK2 as a loading control. (a) Human keratinocytes in FAD medium containing 10 ng/ml EGF were held in suspension or plated for 30 minutes onto dishes coated with poly-L-lysine or the ECM proteins and antibodies shown. (b) Invβ1 mouse keratinocytes were cultured in suspension for 12 hours to induce terminal differentiation and transgene expression and then held in suspension or plated for 30 minutes in the presence of 10 ng/ml EGF onto fibronectin or the human β1–specific antibodies mAb13 and P5D2.

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