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

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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.