Wu Paul W, Li Jing, Kodangattil Sreekumar R, Luxenberg Deborah P, Bennett Frann, Martino Margot, Collins Mary, Dunussi-Joannopoulos Kyriaki, Gill Davinder S, Wolfman Neil M, Fouser Lynette A
Wyeth Research-Inflammation, Cambridge, MA 02140, USA.
J Mol Biol. 2008 Oct 24;382(5):1168-83. doi: 10.1016/j.jmb.2008.07.046. Epub 2008 Jul 25.
Interleukin (IL) 22 is a type II cytokine that is produced by immune cells and acts on nonimmune cells to regulate local tissue inflammation. As a product of the recently identified T helper 17 lineage of CD4(+) effector lymphocytes, IL-22 plays a critical role in mucosal immunity as well as in dysregulated inflammation observed in autoimmune diseases. We used comprehensive mutagenesis combined with mammalian cell expression, ELISA cell-based, and structural methods to evaluate how IL-22 interacts with its cell surface receptor, IL-22R/IL-10R2, and with secreted IL-22 binding protein. This study identifies those amino acid side chains of IL-22 that are individually important for optimal binding to IL-22R, considerably expands the definition of IL-22 surface required for binding to IL-10R2, and demonstrates how IL-22 binding protein prevents IL-22R from binding to IL-22. The IL-22R and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces contributed mostly by helices A, D, and F and loop AB. Our results also provide a model for how IL-19, IL-20, IL-24, and IL-26 which are other IL-10-like cytokines, interact with their respective cell surface receptors.
白细胞介素（IL）-22是一种II型细胞因子，由免疫细胞产生，作用于非免疫细胞以调节局部组织炎症。作为最近鉴定出的CD4(+)效应淋巴细胞辅助性T细胞17亚群的产物，IL-22在黏膜免疫以及自身免疫性疾病中观察到的炎症失调中起关键作用。我们使用全面诱变结合哺乳动物细胞表达、基于ELISA细胞的方法和结构方法，来评估IL-22如何与其细胞表面受体IL-22R/IL-10R2以及分泌型IL-22结合蛋白相互作用。本研究确定了IL-22中对与IL-22R最佳结合分别具有重要作用的那些氨基酸侧链，大大扩展了与IL-10R2结合所需的IL-22表面的定义，并证明了IL-22结合蛋白如何阻止IL-22R与IL-22结合。IL-22R和IL-10R2的结合位点并列在相邻的IL-22表面上，这些表面主要由A、D和F螺旋以及AB环构成。我们的结果还为IL-19、IL-20、IL-24和IL-26（其他IL-10样细胞因子）如何与其各自的细胞表面受体相互作用提供了一个模型。
