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.

IL-17A是许多自身免疫性疾病的治疗靶标。大多数非造血细胞表达IL-17A受体，并通过诱导促炎性细胞因子来应答细胞外IL-17A。IL-17A信号转导触发两个广泛的，依赖TRAF6和TRAF5的细胞内信号传导途径，分别产生代表性的细胞因子（IL-6）和趋化因子（CXCL-1）。我们对这两个分支之间的串扰的有限了解已产生了关键的知识鸿沟，导致治疗剂不加选择地阻断IL-17A并全面抑制其靶基因。在以前的工作中，我们发现炎性主动脉疾病中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，其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信号至关重要。使用经过基因处理的人和小鼠细胞，以及离体和体内大鼠模型，我们发现了14-3-3ζ的功能。作为分子机制的一部分，我们证明14-3-3ζ与几种TRAF蛋白相互作用；这些蛋白与蛋白质的相互作用没有任何关系。特别地，在IL-17A的存在下其与TRAF5和TRAF6的相互作用增加。与TRAF6相反，我们发现TRAF5是IL-17A诱导的IL-6产生的内源性抑制剂，这种作用被14-3-3ζ抵消。此外，我们观察到IL-17A诱导的IL-6水平需要与TRAF蛋白14-3-3ζ相互作用。总之，我们的结果表明14-3-3ζ是IL-17A信号传导和IL-6产生的重要组成部分，TRAF5抑制了这一作用。