title: Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases.
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-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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Farley
authors.forename: David E
authors.initials: DE
authors.lastname: Purdy
authors.forename: Olga P
authors.initials: OP
authors.lastname: Ryabinina
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Magun
authors.forename: Mihail S
authors.initials: MS
authors.lastname: Iordanov
mesh_terms: 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
chemical_list: 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