title: IL-22 and TNF-α represent a key cytokine combination for epidermal integrity during infection with Candida albicans.
abstract: 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.
authors.affiliation: ZAUM-Center for Allergy and Environment, Technische Universität and Helmholtz Center Munich, Munich, Germany. stefanie.eyerich@lrz.tum.de
authors.forename: Stefanie
authors.initials: S
authors.lastname: Eyerich
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wagener
authors.forename: Vera
authors.initials: V
authors.lastname: Wenzel
authors.forename: Claudia
authors.initials: C
authors.lastname: Scarponi
authors.forename: Davide
authors.initials: D
authors.lastname: Pennino
authors.forename: Cristina
authors.initials: C
authors.lastname: Albanesi
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Heidrun
authors.initials: H
authors.lastname: Behrendt
authors.forename: Johannes
authors.initials: J
authors.lastname: Ring
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavani
authors.forename: Martin
authors.initials: M
authors.lastname: Mempel
authors.forename: Claudia
authors.initials: C
authors.lastname: Traidl-Hoffmann
authors.forename: Kilian
authors.initials: K
authors.lastname: Eyerich
mesh_terms: D002176:Candida albicans / Q000276:immunology; D002179:Candidiasis, Cutaneous / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D015923:Complement C1r / Q000378:metabolism; D003173:Complement C1s / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D015151:Immunoblotting; D007378:Interleukins / Q000276:immunology* / Q000502:physiology; D015603:Keratinocytes / Q000276:immunology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000502:physiology; D023083:beta-Defensins / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D018925:Chemokines; D015923:Complement C1r; D003173:Complement C1s; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D000097043:Interleukin-22; C106641:DEFB4A protein, human; C089242:S100A7 protein, human