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J. Biol. Chem., Vol. 278, Issue 22, 19798-19807, May 30, 2003

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Regulation of Interleukin-1 Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease^*

Robin M. Hobbs and Fiona M. Watt 

From the Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Transgenic mice expressing ₁ integrins in the suprabasal epidermal layers have sporadic skin hyperproliferation and inflammation correlated with activation of extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase and increased interleukin (IL)-1 production. We investigated the link between aberrant integrin expression, Erk activation, and expression of IL-1. Transgenic keratinocytes had higher basal Erk activity and IL-1 levels than nontransgenic controls and were more sensitive to stimulation of Erk activity and IL-1 production by IL-1, 12-O-tetradecanoylphorbol-13-acetate (TPA), epidermal growth factor (EGF), and serum. Inhibition of Erk in transgenic keratinocytes reduced basal IL-1 levels and the stimulation of IL-1 production by serum or phorbol ester, demonstrating that Erk could regulate IL-1 expression. TPA or IL-1 treatment resulted in rapid down-regulation of the EGF receptor in transgenic cells, indicative of transactivation. Inhibition of transactivation blocked basal and TPA or IL-1 induced Erk activation, but not IB degradation, and abolished increased IL-1 production in transgenic cells. In transgene-negative cells, constitutive activation of IL-1-dependent signaling by wild type or kinase-dead IRAK1 stimulated IL-1 production independent of Erk. We conclude that suprabasal integrin expression leads to Erk activation and increased IL-1 expression by potentiating activation of the EGF receptor. These results provide a mechanism by which aberrant integrin expression triggers epidermal hyperproliferation and inflammation.

Received for publication, January 16, 2003 , and in revised form, March 21, 2003.

^* This work was supported by Cancer Research UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-20-7269-3528; Fax: 44-20-7269-3078; E-mail: fiona.watt{at}cancer.org.uk.

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