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IL ‐17F regulates psoriasis‐associated genes through IκBζ
Author(s) -
Bertelsen Trine,
Ljungberg Christine,
Boye Kjellerup Rasmus,
Iversen Lars,
Johansen Claus
Publication year - 2017
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13182
Subject(s) - psoriasis , gene silencing , regulator , immune system , biology , interleukin 17 , pathogenesis , immunology , gene , microbiology and biotechnology , genetics
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 si RNA revealed that IκBζ is a key regulator of specific IL ‐17F‐inducible psoriasis‐associated genes and proteins, including DEFB 4/hBD2, S100A7, CCL 20, IL ‐8 and CHI 3L1. 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.