title: Decisive role of tumor necrosis factor-α for spongiosis formation in acute eczematous dermatitis.
abstract: Apoptosis of single keratinocytes (KC) is a characteristic feature of spongiosis formation, the histopathologic hallmark of acute eczematous dermatitis. In acute eczema, activated dermis-infiltrating T cells secrete several proinflammatory cytokines which might be decisive for KC apoptosis or survival. We analyzed the role of tumor necrosis factor alpha (TNF-α) in the determination of KC fate during spongiosis formation in acute eczematous dermatitis. Supernatants of activated human CD4(+) T cells induced apoptosis in primary KC, which could be fully inhibited by individual blockade of interferon-γ (IFN-γ) and CD95 but not by neutralization of TNF-α activity. As compared to CD95-triggering alone, synchronous CD95 and TNF receptor cross-linking in the presence of IFN-γ only marginally enhanced KC apoptosis. Importantly, pre-treatment of KC with TNF-α followed by CD95 stimulation, but not vice versa, significantly amplified KC apoptosis as compared to CD95 stimulation alone. This TNF-α-mediated sensitization to CD95-induced KC cell death could be abrogated by blocking TNF receptor 1 (TNF-R1) but not TNF-R2 mAb. In eczematous dermatitis, the CD95 receptor was expressed throughout the epidermis, whereas immunohistological detection of TNF-R1 was rather restricted to KC around spongiotic vesicle formation. Thus, TNF-α primes KC for CD95-mediated signals which results in an increased susceptibility to apoptosis. TNF-R1 expression and spatial action of TNF-α restricted to spongiotic vesicles promote both CD95-induced KC apoptosis and limitation of spreading KC damage.
authors.affiliation: Department of Dermatology, Venereology, and Allergology, University of Würzburg, Germany. kerstan_a@klinik.uni-wuerzburg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Kerstan
authors.forename: E-B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: A
authors.initials: A
authors.lastname: Trautmann
mesh_terms: D000208:Acute Disease; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D020405:Dermis / Q000473:pathology*; D004485:Eczema / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004487:Edema; D007371:Interferon-gamma / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma