The human IL-17A/F heterodimer regulates psoriasis-associated genes through IκBζ.

Abstract

Antagonists of IL-17A and its receptor have proven to be highly effective in the treatment of psoriasis. However, many of the underlying molecular mechanisms involved in the pathogenesis of psoriasis are still to be determined. IκBζ (encoded by the NFKBIZ gene) plays a key role in the development of psoriasis by mediating IL-17A- and IL-17F-driven effects. Both IL-17A and IL-17F expression are increased in lesional psoriatic skin. IL-17A/A and IL-17F/F homodimers as well as the IL-17A/F heterodimer signal through the same receptors. The aim of this study was to characterize the role of the IL-17A/F heterodimer in the regulation of NFKBIZ expression and in the regulation of selected psoriasis-associated genes. We demonstrated that IL-17A/F stimulation of human keratinocytes significantly induced NFKBIZ expression. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of IL-17A/F-inducible psoriasis-associated genes, including CCL20, DEFB4, IL-8, CHI3L1 and S100A7. In addition, IL-17A/F-induced NFKBIZ expression was mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways. In conclusion, we present IκBζ as a novel key regulator of IL-17A/F-driven effects in psoriasis. Thus, antagonists to IL-17A/F or IκBζ may present a targeted approach for treating psoriasis.

• Authors: Trine Bertelsen, Lars Iversen, Claus Johansen
• Journal: Experimental dermatology (Exp Dermatol) Vol. 27 Issue 9 Pg. 1048-1052 (09 2018) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 29938836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Adaptor Proteins, Signal Transducing
• 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
• S100 Calcium Binding Protein A7
• S100A7 protein, human
• Tumor Necrosis Factor-alpha
• beta-Defensins

Topics

• Adaptor Proteins, Signal Transducing
• Cells, Cultured
• Chemokine CCL20 (genetics)
• Chitinase-3-Like Protein 1 (genetics)
• Gene Expression (drug effects)
• Gene Silencing
• Humans
• I-kappa B Proteins (genetics)
• Interleukin-17 (pharmacology)
• Interleukin-8 (genetics)
• Keratinocytes
• MAP Kinase Signaling System
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics)
• Psoriasis (genetics)
• S100 Calcium Binding Protein A7 (genetics)
• Tumor Necrosis Factor-alpha (pharmacology)
• beta-Defensins (genetics)