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Functional roles of glycans for interaction between cytokines and receptors

聚糖在细胞因子和受体相互作用中的功能作用

基本信息

批准号：
14082208
负责人：
YAMASHITA Katsuko
金额：
$ 48.7万
依托单位：
Tokyo Institute of Technology (2006)Sasaki Institute (2002-2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14082208/
关键词：
high-affinity complex formation GPI-anchored glycan High-mannose type glycan cytokine receptor glycan IL-2 IL-18 TNF-α carbohydrate recognition activity IL-8 チロシンリン酸化ガレクチン-4 硫酸化コレステロールアポトーシスリソソーム酵素分泌硫酸化糖脂質 IL-6 HepG2細胞

项目摘要

Many cytokines recognize unique carbohydrate sequences of various glycoconjugates. Although their functional roles mostly remain to be identified to date, fibroblast growth factor (FGF) had been clearly demonstrated in relation to the physiological activities. We found in this project that various cytokines recognize high-mannose type glycans or GPI-anchor glycans, and following high affinity complex formation with receptor subunits triggers various physiological activities as follows, 1) interleukin-2 (IL-2) binds to both high-mannnose type glycan and a specific peptide sequence in IL-2 receptor α (IL-2Rα), and triggers the formation of high-affinity octamer, (IL-2)_2(IL-2Rα)_2β_2γ_2, and immediately induces cell proliferation. Similar mechanisms were also found to IL-5, IL-6, and IL-8. 2) There exists a group of glycosylphosphatidyl inositol(GPI)-anchored glycan recognizing cytokines, including TNF-α, TNF-β, IL-1β, and IL-18. Interleukin-18 (IL-18) and IL-18 receptor α (IL-18Rα) recognize the distinct GPI-anchored glycan portion of CD48, and the high-affinity octamer formation of (IL-18)_2(CD48)_2(IL-18Rα)_2(IL-18Rβ)_2 triggers the intracellular signal transduction and produces interferon-γ in KG-1 cells. Tumor necrosis factor-α (TNF-α) binds to TNF-α receptor and the second mannose-6-phosphate diester in GPI-anchor glycan. The addition of mmanose-6-phosphate or PI-PLC-treatment on U937 cells diminishes TNF-α inducing apoptosis, indicating that the formation of nanomer, (TNF-α)_3(GPI-glycan)_3(TNFR)_3 triggers various physiological actions. As the results, it was elucidated that such rigid-oligomerization between cytokines and their receptor subunits via the specific glycans is important to modulate immunological response.

许多细胞因子识别各种糖缀合物的独特碳水化合物序列。虽然它们的功能性作用至今大多仍有待确定，但成纤维细胞生长因子（FGF）的生理活性已被清楚地证明。我们在本项目中发现，多种细胞因子识别高甘露糖型聚糖或GPI锚定聚糖，与受体亚基形成高亲和力复合物后触发多种生理活性，具体如下：1）白细胞介素-2（IL-2）与高甘露糖型聚糖和IL-2受体α（IL-2 R α）中的特定肽序列结合，并触发高亲和力八聚体的形成，（IL-2）_2（IL-2 R α）_2β_2γ_2，并立即诱导细胞增殖。也发现了与IL-5、IL-6和IL-8类似的机制。2)存在一组糖基磷脂酰肌醇（GPI）锚定聚糖，识别细胞因子，包括TNF-α、TNF-β、IL-1β和IL-18。在KG-1细胞中，IL-18和IL-18受体α（IL-18 R α）识别CD 48的不同GPI锚定聚糖部分，并形成高亲和力的（IL-18）_2（CD 48）_2（IL-18 R α）_2（IL-18 R β）_2八聚体，触发细胞内信号转导，产生γ-干扰素。肿瘤坏死因子-α（TNF-α）与TNF-α受体和GPI锚定聚糖中的第二个甘露糖-6-磷酸二酯结合。加入6-磷酸甘露糖或磷脂酰肌醇磷脂酰肌醇磷脂酶抑制剂（PI-PLC）处理U937细胞，可减弱TNF-α诱导的细胞凋亡，表明（TNF-α）_3（GPI-glycan）_3（TNFR）_3的形成可引发多种生理作用。结果表明，细胞因子与其受体亚基之间通过特异性聚糖的刚性寡聚化对于调节免疫应答是重要的。