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.

• Authors: Maren Simanski, Franziska Rademacher, Lena Schröder, Hanna Maria Schumacher, Regine Gläser, Jürgen Harder
• Journal: PloS one (PLoS One) Vol. 8 Issue 3 Pg. e59531 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23555696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DEFB103A protein, human
• DEFB4A protein, human
• Interleukin-17
• S100 Calcium Binding Protein A7
• S100 Proteins
• S100A7 protein, human
• STAT3 Transcription Factor
• beta-Defensins
• 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)
• Ribonucleases (genetics, metabolism)
• S100 Calcium Binding Protein A7
• S100 Proteins (genetics)
• STAT3 Transcription Factor (metabolism)
• Staphylococcus aureus (drug effects, physiology)
• beta-Defensins (genetics)