Development of novel anti-inflammation therapy against deglycosylation of proinflammatory cytokine receptors.

针对白细胞介素(IL)-6和肿瘤坏死因子(TNF)- α的抗促炎细胞因子治疗是治疗炎症性疾病的主要进展。我们发现糖酵解抑制剂2-脱氧-d -葡萄糖（2-DG）通过抑制IL-6受体gp130的n -链糖基化来减弱细胞对IL-6的反应。gp130的Aglyco形式无法结合IL-6并激活下游信号。令人惊讶的是，2-DG完全抑制右旋糖酐硫酸钠诱导的结肠炎（炎症性肠病的小鼠模型）。我们发现2-DG还能抑制tnf - α和il -1 β的信号，从而预防另一种炎症性疾病LPS休克的死亡。最后，口服2-DG减轻了人类类风湿关节炎实验模型SKG小鼠的层压蛋白诱导的关节炎。我们的研究结果表明，促炎细胞因子受体的糖基化是减轻炎症反应的潜在靶点。

Anti-proinflammatory cytokine therapies directed against interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha are major advancements in treating inflammatory diseases. We found that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglyco forms of gp130 failed to bind IL-6 and to activate downstream signals. Surprisingly, 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease. We found that 2-DG also inhibited signals for TNF-alpha and IL-1beta, and accordingly prevented death by another inflammatory disease, LPS shock. Finally, orally administered 2-DG alleviated laminarin-induced arthritis in the SKG mouse an experimental model for human rheumatoid arthritis. Our results suggest that glycosylation of proinflammatory cytokine receptors is a potential target to alleviate inflammatory responses.