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J. Biol. Chem., Vol. 283, Issue 2, 919-928, January 11, 2008

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Fas Ligand-induced Proinflammatory Transcriptional Responses in Reconstructed Human Epidermis

RECRUITMENT OF THE EPIDERMAL GROWTH FACTOR RECEPTOR AND ACTIVATION OF MAP KINASES^*

Sherry M. Farley, David E. Purdy, Olga P. Ryabinina, Pascal Schneider, Bruce E. Magun¹, and Mihail S. Iordanov²

From the Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239 and the Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland

Fas ligand (FasL) exerts potent proapoptotic and proinflammatory actions on epidermal keratinocytes and has been implicated in the pathogenesis of eczema, toxic epidermal necrolysis, and drug-induced skin eruptions. We used reconstructed human epidermis to investigate the mechanisms of FasL-induced inflammatory responses and their relationships with FasL-triggered caspase activity. Caspase activity was a potent antagonist of the pro-inflammatory gene expression triggered by FasL prior to the onset of cell death. Furthermore, we found that FasL-stimulated autocrine production of epidermal growth factor receptor (EGFR) ligands, and the subsequent activation of EGFR and ERK1 and ERK2 mitogen-activated protein kinases, were obligatory extracellular steps for the FasL-induced expression of a subset of inflammatory mediators, including CXCL8/interleukin (IL)-8, ICAM-1, IL-1, IL-1β, CCL20/MIP-3, and thymic stromal lymphopoietin. These results expand the known physiological role of EGFR and its ligands from promoting keratinocyte mitogenesis and survival to mediating FasL-induced epidermal inflammation.

Received for publication, July 17, 2007 , and in revised form, September 14, 2007.

^* This work was supported by National Institutes of Health Grants AI059335 and DK066439 (to B. E. M.) and CA-93718 (to M. S. I.) and grants from the Swiss National Science Foundation (to P. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and supplemental Tables S1–S6.

¹ To whom correspondence may be addressed: Dept. of Cell and Developmental Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-7811; Fax: 503-494-4253; E-mail: magunb{at}ohsu.edu. ² To whom correspondence may be addressed: Dept. of Cell and Developmental Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-7811; Fax: 503-494-4253; E-mail: iordanov{at}ohsu.edu.

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