Bertelsen Trine, Ljungberg Christine, Boye Kjellerup Rasmus, Iversen Lars, Johansen Claus
Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
Exp Dermatol. 2017 Mar;26(3):234-241. doi: 10.1111/exd.13182.
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.
银屑病是一种常见的慢性炎症性和免疫介导性皮肤病。肿瘤坏死因子-α拮抗剂以及最近的白细胞介素-17拮抗剂已被证明在银屑病治疗中非常有效；然而，银屑病发病机制中涉及的分子机制仍知之甚少。最近，我们提供了证据表明，IκBζ通过其在介导白细胞介素-17A驱动效应中的作用，是银屑病发展中的关键调节因子。与白细胞介素-17A一样，白细胞介素-17F由多种免疫细胞产生，且在银屑病皮肤中白细胞介素-17F的表达增加。本研究的目的是确定白细胞介素-17F在调节IκBζ表达中的作用，并研究白细胞介素-17F是否通过IκBζ调节人角质形成细胞中与银屑病相关的基因。在此，我们证明白细胞介素-17F刺激可在正常人角质形成细胞中诱导IκBζ在mRNA和蛋白质水平上的表达。此外，通过小干扰RNA沉默IκBζ表明，IκBζ是特定白细胞介素-17F诱导的与银屑病相关的基因和蛋白质的关键调节因子，包括防御素B4/人β-防御素2、S100A7、CCL20、白细胞介素-8和几丁质酶3样蛋白1。此外，白细胞介素-17F诱导的IκBζ表达是由一种涉及p38丝裂原活化蛋白激酶和核因子κB信号通路的机制介导的，这在对这两条信号通路进行化学抑制期间白细胞介素-17F介导的IκBζ表达明显降低中得到了体现。总之，我们提出IκBζ是银屑病中白细胞介素-17F驱动效应的一种新型关键调节因子。因此，IκBζ拮抗剂可能为治疗银屑病以及治疗最近已批准使用白细胞介素-17靶向药物的其他炎症性和免疫介导性疾病提供一种更具针对性的方法。
