Department of Physiology & Pharmacology, College of Medicine & Life Sciences, University of Toledo, Toledo, OH 43614.
Department of Medical Microbiology & Immunology, College of Medicine & Life Sciences, University of Toledo, Toledo, OH 43614.
Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25008-25017. doi: 10.1073/pnas.2008214117. Epub 2020 Sep 23.
IL-17A is a therapeutic target in many autoimmune diseases. Most nonhematopoietic cells express IL-17A receptors and respond to extracellular IL-17A by inducing proinflammatory cytokines. The IL-17A signal transduction triggers two broad, TRAF6- and TRAF5-dependent, intracellular signaling pathways to produce representative cytokines (IL-6) and chemokines (CXCL-1), respectively. Our limited understanding of the cross-talk between these two branches has generated a crucial gap of knowledge, leading to therapeutics indiscriminately blocking IL-17A and global inhibition of its target genes. In previous work, we discovered an elevated expression of 14-3-3 proteins in inflammatory aortic disease, a rare human autoimmune disorder with increased levels of IL-17A. Here we report that 14-3-3ζ is essential for IL-17 signaling by differentially regulating the signal-induced IL-6 and CXCL-1. Using genetically manipulated human and mouse cells, and ex vivo and in vivo rat models, we uncovered a function of 14-3-3ζ. As a part of the molecular mechanism, we show that 14-3-3ζ interacts with several TRAF proteins; in particular, its interaction with TRAF5 and TRAF6 is increased in the presence of IL-17A. In contrast to TRAF6, we found TRAF5 to be an endogenous suppressor of IL-17A-induced IL-6 production, an effect countered by 14-3-3ζ. Furthermore, we observed that 14-3-3ζ interaction with TRAF proteins is required for the IL-17A-induced IL-6 levels. Together, our results show that 14-3-3ζ is an essential component of IL-17A signaling and IL-6 production, an effect that is suppressed by TRAF5. To the best of our knowledge, this report of the 14-3-3ζ-TRAF5 axis, which differentially regulates IL-17A-induced IL-6 and CXCL-1 production, is unique.
白细胞介素 17A（IL-17A）是许多自身免疫性疾病的治疗靶点。大多数非造血细胞表达 IL-17A 受体，并通过诱导促炎细胞因子对细胞外 IL-17A 做出反应。IL-17A 信号转导触发两条广泛的、依赖 TRAF6 和 TRAF5 的细胞内信号通路，分别产生代表性细胞因子（IL-6）和趋化因子（CXCL-1）。我们对这两个分支之间的串扰的理解有限，导致治疗方法不加区分地阻断 IL-17A 并对其靶基因进行全面抑制。在之前的工作中，我们发现在炎症性主动脉疾病中，14-3-3 蛋白的表达升高，这是一种罕见的人类自身免疫性疾病，IL-17A 水平升高。在这里，我们报告 14-3-3ζ 通过差异调节信号诱导的 IL-6 和 CXCL-1 对 IL-17 信号传导至关重要。使用基因工程改造的人类和小鼠细胞以及离体和体内大鼠模型，我们揭示了 14-3-3ζ 的功能。作为分子机制的一部分，我们表明 14-3-3ζ 与几种 TRAF 蛋白相互作用；特别是，在存在 IL-17A 的情况下，它与 TRAF5 和 TRAF6 的相互作用增加。与 TRAF6 相反，我们发现 TRAF5 是内源性抑制 IL-17A 诱导的 IL-6 产生的抑制剂，而 14-3-3ζ 则拮抗这种作用。此外，我们观察到 14-3-3ζ 与 TRAF 蛋白的相互作用是 IL-17A 诱导的 IL-6 水平所必需的。总之，我们的结果表明 14-3-3ζ 是 IL-17A 信号传导和 IL-6 产生的必需组成部分，而这种作用受 TRAF5 抑制。据我们所知，本报告中 14-3-3ζ-TRAF5 轴的作用是独特的，它可差异调节 IL-17A 诱导的 IL-6 和 CXCL-1 的产生。
