CIKS/Act1-mediated signaling by IL-17 cytokines in context: implications for how a CIKS gene variant may predispose to psoriasis.
CIKS/Act1-mediated signaling by IL-17 cytokines in context: implications for how a CIKS gene variant may predispose to psoriasis.
复制标题
DOI：
10.4049/jimmunol.1103233
复制
发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Siebenlist U
中科院分区：
文献类型：
--
作者：
Sønder SU;Paun A;Ha HL;Johnson PF;Siebenlist U
牛皮癣是一种复发性皮肤病，其特征是角质形成细胞异常增殖和分化以及炎症免疫细胞的涌入。最近，IL-17 细胞因子被强烈认为对该疾病的发病机制至关重要。 IL-17A（又名 IL-17）和 IL-17F 是 Th17 细胞的标志性细胞因子，但也由先天细胞产生，包括皮肤中存在的 γδ T 细胞，而上皮细胞（包括角质形成细胞）可能产生 IL-17C。 IL-17 细胞因子通过接头蛋白 CIKS/Act1 发出信号。银屑病是一种具有很强遗传倾向的疾病，编码CIKS的基因最近被确定为易感位点。出乎意料的是，一种易感基因变异具有一种突变，该突变会损害而不是增强 CIKS 介导的 IL-17 细胞因子信号传导，这与 IL-17 细胞因子在银屑病炎症中的预测作用相反。然而，在这里我们证明，如果与 TNFα（一种在银屑病炎症中也很重要的细胞因子）结合，这种突变接头不会损害 IL-17 对遗传反应的特异性贡献。有趣的是，TNFα 信号补偿了这种突变接头造成的 IL-17 信号传导缺陷，甚至对于非 TNFα 单独诱导的基因也是如此，包括转录因子 C/EBPδ 和 IκBδ，它们有助于调节响应 IL-17 的次级基因表达。基于这些发现，我们讨论了一种情况，其中突变接头可能会干扰上皮屏障的稳态维持，从而可能引发对损伤的炎症反应，而一旦 TNFα 存在，该相同的突变接头仍然能够介导 IL-17 特异性的炎症反应。
Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. Recently IL-17 cytokines have been strongly implicated as critical for the pathogenesis of this disease. IL-17A (a.k.a. IL-17) and IL-17F are the signature cytokine of Th17 cells, but are also produced by innate cells, including γδ T cells present in skin, while epithelial cells, including keratinocytes, may produce IL-17C. IL-17 cytokines signal via the adaptor protein CIKS/Act1. Psoriasis is a disease with a strong genetic predisposition and the gene encoding CIKS has recently been identified as a susceptibility locus. Unexpectedly, one predisposing gene variant features a mutation that impairs rather than enhances CIKS-mediated IL-17 cytokine signaling, counter to the predicted role for IL-17 cytokines in psoriatic inflammation. Here we demonstrate, however, that this mutant adaptor does not impair the IL-17-specific contributions to the genetic response if combined with TNFα, a cytokine also prominent in psoriatic inflammation. Interestingly, TNFα signals compensate IL-17 signaling defects imposed by this mutant adaptor even for genes that are not induced by TNFα alone, including the transcription factors C/EBPδ and IκBζ, which help regulate secondary gene expression in response to IL-17. Based on these findings we discuss a scenario in which the mutant adaptor may interfere with homeostatic maintenance of epithelial barriers, thereby potentially enabling the initiation of inflammatory responses to insults, while this same mutant adaptor would still be able to mediate IL-17-specific contributions to inflammation once TNFα is present.
登录
查看更多内容
影响因子：
4.4
作者：
Claudio, Estefania;Sonder, Soren Ulrik;Saret, Sun;Carvalho, Gabrielle;Ramalingam, Thirumalai R.;Wynn, Thomas A.;Chariot, Alain;Garcia-Perganeda, Antonio;Leonardi, Antonio;Paun, Andrea;Chen, Amy;Ren, Nina Y.;Wang, Hongshan;Siebenlist, Ulrich
通讯作者：
Siebenlist, Ulrich
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
100.3
作者：
Dong, C
通讯作者：
Dong, C
DOI：
10.1073/pnas.160265197
发表时间：
2000-09-12
影响因子：
11.1
作者：
Li, XX;Commane, M;Stark, GR
通讯作者：
Stark, GR
影响因子：
6.5
作者：
Chiricozzi, Andrea;Guttman-Yassky, Emma;Krueger, James G.
通讯作者：
Krueger, James G.