IL-17F regulates psoriasis-associated genes through IκBζ.

Abstract

Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-α and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of IκBζ expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL-17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.

• Authors: Trine Bertelsen, Christine Ljungberg, Rasmus Boye Kjellerup, Lars Iversen, Claus Johansen
• Journal: Experimental dermatology (Exp Dermatol) Vol. 26 Issue 3 Pg. 234-241 (03 2017) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 27576147 (Publication Type: Journal Article)
• Copyright: © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Neutralizing
• CCL20 protein, human
• CHI3L1 protein, human
• CXCL8 protein, human
• Chemokine CCL20
• Chitinase-3-Like Protein 1
• DEFB4A protein, human
• I-kappa B Proteins
• IL17A protein, human
• IL17F protein, human
• Interleukin-17
• Interleukin-8
• NF-kappa B
• NFKBIZ protein, human
• Nuclear Proteins
• RNA, Messenger
• RNA, Small Interfering
• S100 Calcium Binding Protein A7
• S100A7 protein, human
• Tumor Necrosis Factor-alpha
• beta-Defensins
• p38 Mitogen-Activated Protein Kinases

Topics

• Adaptor Proteins, Signal Transducing
• Antibodies, Neutralizing (pharmacology)
• Chemokine CCL20 (genetics, metabolism)
• Chitinase-3-Like Protein 1 (genetics, metabolism)
• Gene Expression (drug effects)
• Humans
• I-kappa B Proteins (genetics, immunology, metabolism)
• Interleukin-17 (pharmacology)
• Interleukin-8 (genetics, metabolism)
• Keratinocytes
• MAP Kinase Signaling System
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics, immunology, metabolism)
• Psoriasis (genetics, metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering
• S100 Calcium Binding Protein A7 (genetics, immunology)
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)
• beta-Defensins (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)