Decisive role of tumor necrosis factor-α for spongiosis formation in acute eczematous dermatitis

• Published in: Archives of Dermatological Research 2011-11, Vol.303 (9), p.651-658
• Main Authors: Kerstan, Andreas, Bröcker, E.-B., Trautmann, A.
• Format: Article
• Language: English
• Subjects: Acute Disease; Allergic diseases; Antibodies, Blocking - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Biological and medical sciences; Biopsy; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cells, Cultured; Culture Media, Conditioned - pharmacology; Cytokines - metabolism; Dermatology; Dermis - pathology; Eczema - immunology; Eczema - pathology; Eczema - physiopathology; Edema; fas Receptor - immunology; Immunopathology; Interferon-gamma - immunology; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - metabolism; Keratinocytes - pathology; Lymphocyte Activation; Medical sciences; Medicine; Medicine & Public Health; Original Paper; Receptors, Tumor Necrosis Factor, Type I - immunology; Receptors, Tumor Necrosis Factor, Type II - immunology; Skin allergic diseases. Stinging insect allergies; Skin involvement in other diseases. Miscellaneous. General aspects; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0340-3696; 1432-069X
• DOI: 10.1007/s00403-011-1149-5

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.