Functional roles of glycans for interaction between cytokines and receptors

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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.