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IL-17A and IFN-γ synergistically induce RNase 7 expression via STAT3 in primary keratinocytes.

Abstract
Human keratinocytes produce several antimicrobial peptides and proteins (AMP) which contribute to the protection of human skin against infection. RNase 7 is a major AMP involved in cutaneous defense with a high expression in keratinocytes and a broad spectrum of antimicrobial activity. The cytokine IL-17A has been recently identified as a potent inducer of several AMP in keratinocytes. Since the role of IL-17A to induce RNase 7 expression is unknown we analyzed IL-17A alone and in combination with other cytokines to induce RNase 7 expression in keratinocytes. Whereas IL-17A alone only weakly induced RNase 7 expression, the synergistic combination of IL-17A and IFN-γ (IL-17A/IFN-γ) was identified as a potent inducer of RNase 7 expression. This combination was more effective in inducing RNase 7 than the combination of IL-17A/TNF-α, a combination previously identified as a strong inducer of psoriasis-related immune response genes including several AMP. IFN-γ and IL-17A both have been reported to activate the transcription factor STAT3 (Signal transducer and activator of transcription 3). Therefore we investigated the influence of STAT3 on the IL-17A/IFN-γ -mediated RNase 7 induction. The use of a STAT3 inhibitor as well as siRNA-mediated downregulation of STAT3 resulted in a diminished IL-17A/IFN-γ -mediated RNase 7 induction in keratinocytes indicating that STAT3 is involved in this process. Similarly as seen with RNase 7, treatment of keratinocytes with IL-17A/IFN-γ revealed also a synergistic induction of gene expression of the AMP human beta-defensin (hBD)-2 and -3 as well as the S100 protein psoriasin (S100A7) indicating that the combination of IL-17A/IFN-γ is a potent inducer of various AMP classes in general. This was also reflected by an increase of the Staphylococcus aureus-killing activity of IL-17A/IFN-γ -treated keratinocytes.
AuthorsMaren Simanski, Franziska Rademacher, Lena Schröder, Hanna Maria Schumacher, Regine Gläser, Jürgen Harder
JournalPloS one (PLoS One) Vol. 8 Issue 3 Pg. e59531 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23555696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DEFB4A protein, human
  • Interleukin-17
  • S100 Proteins
  • S100A7 protein, human
  • STAT3 Transcription Factor
  • beta-Defensins
  • beta-defensin 3, human
  • Interferon-gamma
  • Ribonucleases
  • Ribonuclease 7
Topics
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Humans
  • Interferon-gamma (pharmacology)
  • Interleukin-17 (pharmacology)
  • Keratinocytes (drug effects, metabolism, microbiology, secretion)
  • Ribonucleases (genetics, metabolism, secretion)
  • S100 Proteins (genetics)
  • STAT3 Transcription Factor (metabolism)
  • Staphylococcus aureus (drug effects, physiology)
  • beta-Defensins (genetics)

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