Functional roles of glycans for interaction between cytokines and receptors

许多细胞因子识别各种糖缀合物的独特碳水化合物序列。尽管到目前为止，它们的功能作用仍有待确定，但成纤维细胞生长因子（FGF）已被清楚地证明与生理活动有关。本研究发现，多种细胞因子识别高甘露糖型聚糖或GPI-anchor聚糖，并与受体亚基形成高亲和力复合物，引发多种生理活动：1)白细胞介素-2 （IL-2）结合高甘露糖型聚糖和IL-2受体α (IL-2Rα)的特定肽序列，引发高亲和力八聚体（IL-2）_2(IL-2Rα)_2β_2γ_2的形成，并立即诱导细胞增殖。IL-5、IL-6和IL-8也发现了类似的机制。2)存在一组糖基磷脂酰肌醇（GPI）锚定的聚糖识别细胞因子，包括TNF-α、TNF-β、IL-1β和IL-18。白细胞介素-18 （IL-18）和IL-18受体α (IL-18Rα)识别CD48的gpi特异性糖基部分，在KG-1细胞中形成（IL-18）_2(CD48)_2(IL-18Rα)_2(IL-18Rβ)_2的高亲和力八聚体，触发细胞内信号转导并产生干扰素-γ。肿瘤坏死因子-α (TNF-α)结合TNF-α受体和gpi锚定聚糖中的甘露糖-6-磷酸二酯。在U937细胞上添加寡糖-6-磷酸或pi - plc处理后，诱导凋亡的TNF-α减少，表明纳米体（TNF-α）_3（gpi -聚糖）_3(TNFR)_3的形成触发了多种生理作用。结果表明，细胞因子及其受体亚基之间的这种刚性寡聚化通过特定的聚糖来调节免疫反应是重要的。

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.