Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity
Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity
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DOI：
10.4049/jimmunol.166.12.7096
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发表时间：
2001-06-15
影响因子：
4.4
通讯作者：
Pestka, S
中科院分区：
文献类型：
--
作者：
Kotenko, SV;Izotova, LS;Pestka, S
（W）利用人类基因组的部分序列，我们鉴定了编码属于II类细胞因子受体家族的新型可溶性受体的基因。该基因位于染色体6上，在IFNGR 1基因附近，以头到高的方向。该基因由6个外显子组成，编码一个231个氨基酸的蛋白质，其中有一个21个氨基酸的前导序列。分泌的成熟蛋白质与IL-22 R1链的胞外结构域具有34%的氨基酸同一性。交联实验表明，该蛋白结合IL-22并阻止IL-22与功能性细胞表面IL-22 R复合物结合，该复合物由两个亚基IL-22 R1和IL-10 R2组成（c）。店此外，这种可溶性受体，称为IL-22结合蛋白（BP），能够中和IL-22活性。在IL-22 BP存在下，IL-22不能诱导IL-22应答性人肺癌A549细胞中的Stat活化。IL-22 BP还阻断了HepG 2细胞中IL-22对细胞因子信号传导抑制因子-3（SOCS-3）基因表达的诱导。为了进一步评价IL-22 BP的作用，我们使用表达修饰的IL-22 R复合物的仓鼠细胞，所述修饰的IL-22 R复合物由完整的IL-10 R2（c）和嵌合的IL-22 R1/γ R1受体组成，其中IL-22 R1胞内结构域被IFN-γ R1胞内结构域替换。在这些细胞中，IL-22激活IFN-γ特异性的生物活性，例如上调MHC I类Ag表达。IL-22 BP的加入中和了IL-22诱导这些细胞中Stat活化和MHC I类Ag表达的能力。因此，命名为IL-22 BP的可溶性受体通过结合IL-22并阻断其与细胞表面IL-22 R复合物的相互作用来抑制IL-22活性。
(W)ith the use of a partial sequence of the human genome, we identified a gene encoding a novel soluble receptor belonging to the class II cytokine receptor family. This gene is positioned on chromosome 6 in the vicinity of the IFNGR1 gene in a head-to-tall orientation. The gene consists of six exons and encodes a 231-aa protein with a 21-aa leader sequence. The secreted mature protein demonstrates 34% amino acid identity to the extracellular domain of the IL-22R1 chain. Cross-linking experiments demonstrate that the protein binds IL-22 and prevents binding of IL-22 to the functional cell surface IL-22R complex, which consists of two subunits, the IL-22R1 and the IL-10R2(c). chains. Moreover, this soluble receptor, designated IL-22-binding protein (BP), is capable of neutralizing IL-22 activity. In the presence of the IL-22BP, IL-22 is unable to induce Stat activation in IL-22-responsive human lung carcinoma A549 cells. IL-22BP also blocked induction of the suppressors of cytokine signaling-3 (SOCS-3) gene expression by IL-22 in HepG2 cells. To further evaluate IL-22BP action, we used hamster cells expressing a modified IL-22R complex consisting of the intact IL-10R2(c) and the chimeric IL-22R1/gamma R1 receptor in which the IL-22R1 intracellular domain was replaced with the IFN-gamma R1 intracellular domain. In these cells, IL-22 activates biological activities specific for IFN-gamma, such as up-regulation of MHC class I Ag expression. The addition of IL-22BP neutralizes the ability of IL-22 to induce Stat activation and MHC class I Ag expression in these cells. Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity by binding IL-22 and blocking its interaction with the cell surface IL-22R complex.