title: Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes: implications for dermatitis.
abstract: Fas ligand (FasL) causes apoptosis of epidermal keratinocytes and triggers the appearance of spongiosis in eczematous dermatitis. We demonstrate here that FasL also aggravates inflammation by triggering the expression of proinflammatory cytokines, chemokines, and adhesion molecules in keratinocytes. In HaCaT cells and in reconstructed human epidermis (RHE), FasL triggered a NF-kappaB-dependent mRNA accumulation of inflammatory cytokines (tumor necrosis factor-alpha, IL-6, and IL-1beta), chemokines (CCL2/MCP-1, CXCL1/GROalpha, CXCL3/GROgamma, and CXCL8/IL-8), and the adhesion molecule ICAM-1. Oligomerization of Fas was required both for apoptosis and for gene expression. Inhibition of caspase activity abolished FasL-dependent apoptosis; however, it failed to suppress the expression of FasL-induced genes. Additionally, in the presence of caspase inhibitors, but not in their absence, FasL triggered the accumulation of CCL5/RANTES (regulated on activation normal T cell expressed and secreted) mRNA. Our findings identify a novel proinflammatory role of FasL in keratinocytes that is independent of caspase activity and is separable from apoptosis. Thus, in addition to causing spongiosis, FasL may play a direct role in triggering and/or sustaining inflammation in eczemas.
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: Anjali D
authors.initials: AD
authors.lastname: Dotson
authors.forename: David E
authors.initials: DE
authors.lastname: Purdy
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Sundholm
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 / Q000235:genetics; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000209:etiology* / Q000235:genetics; D004485:Eczema / Q000209:etiology* / Q000235:genetics; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D015815:Cell Adhesion Molecules; D018925:Chemokines; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D053222:Fas Ligand Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D020169:Caspases