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

• Published in: European journal of immunology 2011-07, Vol.41 (7), p.1894-1901
• Main Authors: Eyerich, Stefanie, Wagener, Jeanette, Wenzel, Vera, Scarponi, Claudia, Pennino, Davide, Albanesi, Cristina, Schaller, Martin, Behrendt, Heidrun, Ring, Johannes, Schmidt‐Weber, Carsten B., Cavani, Andrea, Mempel, Martin, Traidl‐Hoffmann, Claudia, Eyerich, Kilian
• Format: Article
• Language: English
• Subjects: beta-Defensins - metabolism; Candida albicans; Candida albicans - immunology; Candidiasis, Cutaneous - immunology; Chemokines - metabolism; Complement C1r - metabolism; Complement C1s - metabolism; Enzyme-Linked Immunosorbent Assay; Epidermal integrity; Epidermis - immunology; Humans; IL‐22; Immunity, Innate; Immunoblotting; Interleukin-22; Interleukins - immunology; Interleukins - physiology; Keratinocytes - immunology; Male; Mitogen-Activated Protein Kinases - metabolism; Polymerase Chain Reaction; S100 Calcium Binding Protein A7; S100 Proteins - metabolism; T-Lymphocytes, Helper-Inducer - immunology; TNF‐α; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201041197

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.