Günther Sebastian, Sundberg Eric J
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201
J Immunol. 2014 Jul 15;193(2):921-30. doi: 10.4049/jimmunol.1400538. Epub 2014 Jun 16.
The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.
白细胞介素-1（IL-1）家族由11种细胞因子组成，这些细胞因子控制着一个复杂的促炎信号网络，该网络对于调节对感染的免疫反应至关重要。它们在众多慢性炎症性疾病中也发挥着核心作用。因此，抑制这些细胞因子的活性是治疗自身免疫性疾病和淋巴瘤的重要治疗策略。IL-1家族中的激动剂细胞因子通过结合其同源受体并随后募集受体辅助蛋白来激活信号传导。相反，拮抗剂细胞因子结合其同源受体但阻止受体辅助蛋白的募集，从而排除功能性信号复合物。细胞因子的IL-36亚家族是最多样化的，包括三种激动剂和至少一种拮抗剂，并且是该家族中特征最少的一组。通过IL-36受体的信号传导直接刺激树突状细胞并使初始CD4 T细胞引发Th1反应。适当平衡的IL-36信号传导是皮肤和肺部健康的关键决定因素。IL-36信号传导被认为与IL-1信号传导类似地发挥作用。在这项研究中，我们已经确定了通过IL-36受体的激动剂和拮抗剂信号传导的分子决定因素。我们展示了IL-36γ的晶体结构，据我们所知，这是首次报道的IL-36激动剂的结构。以该结构为指导，我们设计了一系列全面的IL-36激动剂/拮抗剂嵌合蛋白，我们测量了它们与IL-36受体/IL-1受体辅助蛋白复合物的结合以及信号传导的功能激活和抑制。我们的数据揭示了IL-36信号传导的精细特异性如何与IL-1的不同。
