Journal Article

2‐Deoxy‐d‐glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation

Tanaka, Nobuyuki, Onda, Munehiko, Taki, Shinsuke, Hida, Shigeaki, Tanimura, Atsuko, Kajita, Mitsuko, Uehara, Ikuno, Naito, Zenya

2022

Overview

Anti‐proinflammatory cytokine therapies against interleukin (IL)‐6, tumor necrosis factor (TNF)‐α, and IL‐1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2‐deoxy‐d‐glucose (2‐DG), a simple monosaccharide, attenuated cellular responses to IL‐6 by inhibiting N‐linked glycosylation of the IL‐6 receptor gp130. Aglycoforms of gp130 did not bind to IL‐6 or activate downstream intracellular signals that included Janus kinases. 2‐DG completely inhibited dextran sodium sulfate‐induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin‐induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL‐6. We also found that 2‐DG inhibited signals for other proinflammatory cytokines such as TNF‐α, IL‐1β, and interferon ‐γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2‐DG prevented LPS shock, a model for a cytokine storm, and LPS‐induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID‐19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases. The glycolytic inhibitor 2‐deoxy‐D‐glucose attenuated cellular responses to proinflammatory cytokines by inhibiting N‐linked glycosylation of their receptors and alleviated the signs and symptoms of mouse models for inflammatory bowel disease, rheumatoid arthritis, cytokine storm, and acute respiratory distress syndrome.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: 2‐Deoxy‐d‐glucose (2‐DG) / Animals / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Cells, Cultured / Coronaviruses / COVID-19 / Cytokine Receptor gp130 - antagonists & inhibitors / Cytokine Receptor gp130 - metabolism / Cytokine Release Syndrome - prevention & control / cytokine storm / Cytokines - metabolism / deglycosylation / Deoxyglucose - pharmacology / Glycosylation - drug effects / Inflammation / Inflammation - chemically induced / Inflammation - prevention & control / Inflammatory bowel disease / inflammatory diseases / Janus Kinases - drug effects / Lipopolysaccharides / Mice / Mice, Inbred C57BL / Mice, Knockout / Original / Pharmacology / proinflammatory cytokine receptors / Receptors, Cytokine - drug effects / Receptors, Cytokine - immunology / Receptors, Cytokine - metabolism / Receptors, Interleukin-6 - antagonists & inhibitors / Receptors, Interleukin-6 - genetics / Receptors, Interleukin-6 - metabolism / rheumatoid arthritis / Tumor necrosis factor-TNF