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The human IL ‐17A/F heterodimer regulates psoriasis‐associated genes through IκBζ
Author(s) -
Bertelsen Trine,
Iversen Lars,
Johansen Claus
Publication year - 2018
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.13722
Subject(s) - psoriasis , interleukin 17 , gene silencing , regulator , signal transduction , gene , receptor , pathogenesis , microbiology and biotechnology , biology , chemistry , immunology , genetics , immune system
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 si RNA revealed that IκBζ is a key regulator of IL ‐17A/F‐inducible psoriasis‐associated genes, including CCL 20, DEFB 4, IL ‐8, CHI 3L1 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.