Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases.
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-1alpha, IL-1beta, CCL20/MIP-3alpha, 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.
Farley
Sherry M
SM
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Purdy
David E
DE
Ryabinina
Olga P
OP
Schneider
Pascal
P
Magun
Bruce E
BE
Iordanov
Mihail S
MS
D017209:Apoptosis; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D004817:Epidermis / Q000503:physiopathology*; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000503:physiopathology*; D015603:Keratinocytes / Q000502:physiology*; D007668:Kidney; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic
D017931:DNA Primers; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3