Hobbs, Robin Mark; (2003) A role for mitogen-activated protein kinase in epidermal hyperproliferation and inflammation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Keratinocytes in the basal layer of epidermis express β1 integrins which have been shown in vitro to regulate proliferation and differentiation via MAPK activation. In hyperproliferative epidermis, such as in psoriasis or during wound healing, β1 integrins are also present in the suprabasal layers. Suprabasal integrin expression in transgenic mice generates sporadic psoriatic-like lesions demonstrating that integrin mis-expression in the epidermis can trigger hyperproliferation and inflammation. In my thesis I demonstrate that suprabasal β1 integrin expression correlates with MAPK activation in hyperproliferative lesions from psoriatic patients and from the suprabasal β1 integrin transgenic mouse. To establish a role for suprabasal MAPK activation in epidermal hyperproliferation and inflammation I have generated transgenic mice expressing an activated MEK1 construct from the involucrin promoter. These mice show both a hyperproliferative epidermis and an inflammatory infiltrate. At sites of abrasion some of the mice go on to develop papillomas. Keratinocytes from β1 integrin transgenic mice express increased levels of the pro-inflammatory cytokine interleukin-1α (IL-1α) compared to controls. The increased IL-1α could explain the lymphocyte recruitment observed in the lesions of the transgenic mice. From in vitro work I show that MAPK itself can regulate both basal and induced IL-1α expression. Cells from integrin transgenic mice show an increased sensitivity to IL-1α-inducing stimuli, particularly phorbol ester. Treatment with phorbol ester generates a much more sustained MAPK activation in the transgene-positive cells compared to controls. Furthermore, I demonstrate critical roles for epidermal growth factor receptor activity and autocrine IL-1α signalling in regulation of IL-1α levels in the cells. From these experiments I propose a model in which MAPK activation plays a central role in both the epidermal hyperproliferation and cutaneous inflammation characteristic of psoriasis.

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