Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
Exp Dermatol. 2018 Sep;27(9):1048-1052. doi: 10.1111/exd.13722. Epub 2018 Jul 29.
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.
白细胞介素-17A（IL-17A）及其受体的拮抗剂已被证明在治疗银屑病方面非常有效。然而，银屑病发病机制中涉及的许多潜在分子机制仍有待确定。IκBζ（由 NFKBIZ 基因编码）通过介导 IL-17A 和 IL-17F 驱动的作用，在银屑病的发展中发挥关键作用。病变银屑病皮肤中 IL-17A 和 IL-17F 的表达均增加。IL-17A/A 和 IL-17F/F 同源二聚体以及 IL-17A/F 异源二聚体通过相同的受体信号转导。本研究旨在表征 IL-17A/F 异源二聚体在调节 NFKBIZ 表达和调节选定的银屑病相关基因中的作用。我们证明，IL-17A/F 刺激人角质形成细胞可显著诱导 NFKBIZ 表达。此外，通过 siRNA 沉默 IκBζ 表明 IκBζ 是 IL-17A/F 诱导的银屑病相关基因（包括 CCL20、DEFB4、IL-8、CHI3L1 和 S100A7）的关键调节剂。此外，IL-17A/F 诱导的 NFKBIZ 表达是通过涉及 p38 MAPK 和 NF-κB 信号通路的机制介导的。总之，我们提出 IκBζ 是银屑病中 IL-17A/F 驱动作用的新的关键调节剂。因此，IL-17A/F 或 IκBζ 的拮抗剂可能为治疗银屑病提供一种靶向方法。
