title: TNF-α and IFN-γ are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis.
abstract: Toxic epidermal necrolysis (TEN) is a severe immune-mediated adverse cutaneous drug eruption characterized by rapid and extensive epithelial cell death in the epidermis and mucosae. The molecular events leading to this often fatal condition are only partially understood, but evidence suggests a dual mechanism implicating a "drug"-specific immune response on one side and the onset of target cell death by proapoptotic molecules including FasL on the other side. Herein, we describe a potential molecular bridge between these two events that involves inducible nitric oxide synthase (iNOS), which is highly upregulated in the skin of TEN patients. We show that activated T cells secrete high amounts of tumor necrosis factor-α (TNF-α) and IFN-γ, and that both cytokines lead to increased expression and activity of keratinocyte iNOS. A similar observation has been made with drug-specific T lymphocytes from a TEN patient exposed to the culprit drug. The resulting increase in nitric oxide significantly upregulates keratinocyte FasL expression, resulting in Fas- and caspase-8-mediated keratinocyte cell death. Taken together, our data suggest that T-lymphocyte activation by drugs in TEN patients may indirectly lead to FasL-mediated keratinocyte apoptosis, via a molecular bridge involving TNF-α, IFN-γ, and iNOS.
authors.affiliation: IVL BioService, Saint-Barthélémy, Le Gua, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Viard-Leveugle
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaide
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Laurence
authors.initials: L
authors.lastname: Feldmeyer
authors.forename: Katrin
authors.initials: K
authors.lastname: Kerl
authors.forename: Chris
authors.initials: C
authors.lastname: Pickard
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roques
authors.forename: Peter S
authors.initials: PS
authors.lastname: Friedmann
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Contassot
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D013262:Stevens-Johnson Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C505530:CASP8 protein, human; D053181:Caspase 8