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IL‐22 and TNF‐α represent a key cytokine combination for epidermal integrity during infection with Candida albicans

2011; Wiley; Volume: 41; Issue: 7 Linguagem: Inglês

10.1002/eji.201041197

1521-4141

Stefanie Eyerich, Jeanette Wagener, Vera Wenzel, Claudia Scarponi, Davide Pennino, Cristina Albanesi, Martin Schaller, Heidrun Behrendt, Johannes Ring, Carsten B. Schmidt‐Weber, Andrea Cavani, Martin Mempel, Claudia Traidl‐Hoffmann, Kilian Eyerich,

T-cell and B-cell Immunology

T cells exercise their full impact on target cells through a combination of secreted cytokines. The recently described T helper cell subset Th22 is characterized by a combinatorial secretion of IL-22 and TNF-α. Here, we demonstrate that IL-22 increases the TNF-α-dependent induction and secretion of several immune-modulatory molecules such as initial complement factors C1r and C1s, antimicrobial peptides S100A7 and HBD-2 (human β defensin 2), and antimicrobial chemokines CXCL-9/-10/-11 in primary human keratinocytes. The synergism of IL-22 and TNF-α is transmitted intracellularly by MAP kinases and downstream by transcription factors of the AP-1 family. The induction of innate immunity is relevant in an in vitro infection model, where keratinocytes stimulated with Th22 supernatants or recombinant IL-22 plus TNF-α effectively inhibit the growth of Candida albicans and maintain survival of epithelia. Accordingly, the combinatorial stimulation of keratinocytes with IL-22 and TNF-α most efficiently conserves the integrity of the epidermal barrier in a three-dimensional skin infection model as compared with IFN-γ, IL-17, IL-22 or TNF-α alone. In summary, we demonstrate that IL-22 and TNF-α represent a potent, synergistic cytokine combination for cutaneous immunity.