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.
View: Text | PDF
Article

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

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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Proinflammatory cytokine production and cytokine-induced MAPK phosphoryl...
Proinflammatory cytokine production and cytokine-induced MAPK phosphorylation. Secretion of IL-1α (a), IL-1β (c), and IL-6 (d) by nontransgenic (open bars) and α2β1 transgene-expressing (filled bars) mouse keratinocytes. Intracellular IL-1α levels are shown in b. In the case of overnight keratinocyte/feeder cocultures (o/n coculture), cytokine secreted represents the total produced by both cell types, whereas intracellular levels were measured in keratinocytes alone. (e) Western blot analysis of ERK1/2 and p38 MAPK phosphorylation (P-ERK1/2 and P-p38 MAPK, respectively) and total ERK2 and p38 MAPK. Preconfluent human keratinocytes had feeders removed and were starved overnight before a 15-minute stimulation with medium alone (FAD) or medium supplemented with IL-1α/β, IL-6, or EGF alone or in combinations. IL-1 α/β and IL-6 were added to a final concentration of 10 ng/ml while EGF was added to 10 ng/ml when the only cytokine present (10 EGF) or 0.1 ng/ml when used in combination with other cytokines (0.1 EGF).