Department of Dermatology, Aarhus University Hospital, DK-8200 Aarhus, Denmark.
Acta Derm Venereol. 2021 Feb 9;101(2):adv00386. doi: 10.2340/00015555-3749.
The interleukin (IL)-36 cytokine family plays an essential role in inflammatory processes in the skin and is implicated in the pathogenesis of psoriasis. This study explored the role of IL-36 in psoriasis and investigated the molecular mechanism involved in tumour necrosis factor-α (TNFα)/IL-17A-mediated IL-36 induction. In human keratinocytes IL-36 expression was strongly upregulated by combined TNFα and IL-17A stimulation. Moreover, IκBζ, encoded by NFKBIZ, was identified as a key regulator required for TNFα/IL-17A-induced IL-36γ expression. TNFα/IL-17A-induced IL-36γ expression also involved the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase and ERK1/2 signalling pathways. Furthermore, a specific NF-κB DNA-binding site in the promoter region of IL36G responsible for the TNFα/IL-17A-induced IL36G gene expression was identified. Finally, in a cohort of patients with psoriasis receiving anti-IL-17A treatment, a positive correlation was found between the expression of NFKBIZ and IL36G. In conclusion, these data reveal a novel crucial regulatory mechanism by which TNFα and IL-17A regulate IL-36γ expression.
白细胞介素 (IL)-36 细胞因子家族在皮肤炎症过程中发挥着重要作用，并与银屑病的发病机制有关。本研究探讨了 IL-36 在银屑病中的作用，并研究了肿瘤坏死因子-α (TNFα)/IL-17A 介导的 IL-36 诱导所涉及的分子机制。在人角质形成细胞中，TNFα 和 IL-17A 的联合刺激强烈地上调了 IL-36 的表达。此外，由 NFKBIZ 编码的 IκBζ 被鉴定为 TNFα/IL-17A 诱导的 IL-36γ 表达所必需的关键调节因子。TNFα/IL-17A 诱导的 IL-36γ 表达还涉及核因子 κB (NF-κB)、p38 丝裂原活化蛋白激酶和 ERK1/2 信号通路。此外，还确定了负责 TNFα/IL-17A 诱导的 IL36G 基因表达的 IL36G 启动子区域中 NF-κB 的特定 DNA 结合位点。最后，在接受抗 IL-17A 治疗的银屑病患者队列中，发现 NFKBIZ 和 IL36G 的表达之间存在正相关。总之，这些数据揭示了 TNFα 和 IL-17A 调节 IL-36γ 表达的新的关键调节机制。
