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. Magun; Mihail S. Iordanov

doi:10.1074/jbc.M705852200

Fas Ligand-induced Proinflammatory Transcriptional Responses in Reconstructed Human Epidermis

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

^‡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

↵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.

Abstract

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-1α, IL-1β, CCL20/MIP-3α, 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.