TY - JOUR
T1 - Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis
T2 - Recruitment of the epidermal growth factor receptor and activation of MAP kinases
AU - Farley, Sherry M.
AU - Purdy, David E.
AU - Ryabinina, Olga P.
AU - Schneider, Pascal
AU - Magun, Bruce E.
AU - Iordanov, Mihail S.
PY - 2008/1/11
Y1 - 2008/1/11
N2 - 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,wefound 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 thymicstromal 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.
AB - 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,wefound 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 thymicstromal 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.
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U2 - 10.1074/jbc.M705852200
DO - 10.1074/jbc.M705852200
M3 - Article
C2 - 17977827
AN - SCOPUS:38149030231
SN - 0021-9258
VL - 283
SP - 919
EP - 928
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -