Division of Rheumatic and Musculoskeletal Disease, Leeds Institute of Molecular Medicine, LMBRU LTHT, University of Leeds, Leeds, United Kingdom.
PLoS One. 2012;7(6):e38751. doi: 10.1371/journal.pone.0038751. Epub 2012 Jun 27.
IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48-72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts.
白细胞介素-18 (IL-18) 是一种重要的介质，参与慢性炎症性疾病，如皮肤红斑狼疮、银屑病和慢性湿疹。IL-18 与其内源性拮抗剂白细胞介素-18 结合蛋白 (BP) 之间的失衡可能导致 IL-18 活性增加。白细胞介素-27 (IL-27) 是一种具有双重功能的细胞因子，具有促炎和抗炎特性。在这里，我们提供了关于其对皮肤常驻细胞具有抗炎作用的证据。人角质形成细胞，甚至出人意料的是成纤维细胞（不产生任何 IL-18），在受到 IL-27 刺激后，会显示出强大的、剂量依赖性的、高度诱导的 IL-18BP mRNA 表达和分泌。其他白细胞介素-12 家族成员则不能诱导 IL-18BP。IL-18BP 的产生在刺激后 48-72 小时达到峰值，并可持续长达 96 小时。对信号通路的研究表明，IL-27 在人角质形成细胞中激活 STAT1，而 IL-18BP 启动子上的近端 GAS 位点对于 IL-27 的功能活性很重要。这些数据支持了 IL-27 对皮肤常驻细胞具有显著的抗炎作用。IL-27 在皮肤病理生物学中的一个重要新特性可能是通过作用于角质形成细胞，重要的是也作用于真皮成纤维细胞，来拮抗 IL-18 的活性。
