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

Eur J Immunol. 2011 Jul;41(7):1894-901. doi: 10.1002/eji.201041197. Epub 2011 May 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Candida albicans / immunology
  • Candidiasis, Cutaneous / immunology*
  • Chemokines / metabolism
  • Complement C1r / metabolism
  • Complement C1s / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Epidermis / immunology*
  • Humans
  • Immunity, Innate
  • Immunoblotting
  • 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
  • Transcription Factor AP-1 / metabolism
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / physiology
  • beta-Defensins / metabolism

Substances

  • Chemokines
  • DEFB4A protein, human
  • Interleukins
  • S100 Calcium Binding Protein A7
  • S100 Proteins
  • S100A7 protein, human
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • beta-Defensins
  • Mitogen-Activated Protein Kinases
  • Complement C1r
  • Complement C1s
  • interleukin-22