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Cytokines recognizing GPI-anchored glycan

识别 GPI 锚定聚糖的细胞因子

基本信息

批准号：
15570129
负责人：
FUKUSHIMA Keiko
金额：
$ 1.86万
依托单位：
Sasaki Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

A variety of cytokines have been reported to be able to recognize specific carbohydrate moieties. I have found that several cytokines including IL-1β,TNF-α,IL-18 can recognize GPI-anchored glycan. In this research, I investigated whether the carbohydrate recognition by these cytokines can modulate their physiological activities, (i)The stimulation of the apoptosis o human lymphoma U937 cells by TNF-α was inhibited by treatment with mannose 6-phosphate or phosphatidyl inositol-speciic phospholipase C (PI-PLC). These results suggest that TNF-α bindig to the GPI-anchore glycan, along with its binding to TNF-α receptor, triggers the intracellular signaling pathway in U937 cells, (ii)I found that IL-18 and IL-18Rα bind to GPI glycan via the third mannose 6-phosphate diester and the second β-GlcNAc-deleted mannose 6-phosphate of GPI-glycan, respectively. To investigate whether the carbohydrate recognition of IL-18 is involved in physiological activities, KG-1 cells were digested with PI-PLC before IL-18 stimulation. PI-PLC treatment inhibited the phosphorylation of tyrosine kinases and the following IL-18 dependent IFN-γ production. Moreover, IL-18Receptor α subunit of IL-18 stimulated KG-1 cells was immunoprecipitated together CD48 by anti-IL-18Rα antibody. These observations suggest that the complex formation of IL-18/IL-18Rα/CD48 via both the peptide portion and GPI glycan triggers the binding to IL-18Rβ, and IL-18/IL-18Rα/CD48/IL-18Rβ complex induces cellular signaling.

据报道，多种细胞因子能够识别特定的碳水化合物部分。我发现包括IL-1β、肿瘤坏死因子-α、IL-18在内的几种细胞因子都能识别GPI锚定的糖链。在这项研究中，我研究了这些细胞因子对糖的识别是否可以调节它们的生理活性。(1)甘露糖6-磷酸或磷脂酰肌醇特异性磷脂酶C(PI-α)可抑制肿瘤坏死因子对人淋巴瘤U937细胞的促凋亡作用。(2)IL-18和IL-18Rα分别通过第三个甘露糖6-磷酸二酯和第二个缺失甘露糖6-磷酸的甘露糖6-α与GPI-α结合。为探讨IL-18的糖识别是否参与生理活动，在IL-18刺激前用PI-PLC消化KG-1细胞。PI-PLC处理可抑制酪氨酸激酶的磷酸化和随后IL-18依赖的干扰素-γ的产生。此外，IL-18刺激的KG-1细胞的IL-18受体α亚基被抗IL-18Rα抗体免疫共沉淀。这些结果表明，IL-18/IL-18Rα/CD48通过肽部分和糖链形成复合体，触发与IL-18Rβ的结合，而IL-18/IL-18Rα/CD48/IL-18Rβ复合体诱导细胞信号转导。