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

Abstract

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.

Statins Show Anti-Atherosclerotic Effects by Improving Endothelial Cell Function in a Kawasaki Disease-like Vasculitis Mouse Model

“…Aortic tissue from the ascending aorta to the bifurcation collected at sacrifice was shredded and proteins harvested as previously described [60,61]. Briefly, to harvest proteins, 0.5 mL RIPA buffer containing protease inhibitor and no Triton X-100 was added to the tissue, and the tissue homogenized for 5 min at the highest frequency using Tissue Lyser II (Qiagen, Venlo, Nederland).…”

The Impact of Glycolysis and Its Inhibitors on the Immune Response to Inflammation and Autoimmunity

“…However, they usually need to be used with other “disease-modifying” strategies to control chronic inflammatory disorders effectively [ 41 ]. Recently, anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 were introduced in inflammatory disease therapy, especially for rheumatoid arthritis [ 42 ]. Such therapies are mainly performed using monoclonal antibodies against cytokines or cytokine receptors.…”

“…Recent studies published by Uehara et al [ 42 ] showed that 2-DG significantly attenuated the proinflammatory response to IL-6 by inhibiting IL-6R gp130 glycosylation. 2-DG also blocked signals induced by TNF-α, IL-1β, and interferon (IFN)-γ, efficiently alleviating a mouse model of inflammatory bowel disease and human rheumatoid arthritis.…”

“…2-DG also blocked signals induced by TNF-α, IL-1β, and interferon (IFN)-γ, efficiently alleviating a mouse model of inflammatory bowel disease and human rheumatoid arthritis. Further, 2-DG also attenuated lipopolysaccharide (LPS)-induced pulmonary inflammatory responses in a mouse model of a cytokine storm and Acute Respiratory Distress Syndrome (ARDS) [ 42 ]. The authors concluded that the N-glycosylation of proinflammatory cytokine receptors is an unrecognized potential target for anti-inflammatory therapies.…”

2-Deoxy-D-Glucose: A Novel Pharmacological Agent for Killing Hypoxic Tumor Cells, Oxygen Dependence-Lowering in Covid-19, and Other Pharmacological Activities

“…2-DG reduces the infammatory responses triggered by glycogen accumulation caused by coal dust because macrophages have reconstituted glycogen metabolism [27]. A study on dextran sulfate sodium-induced colitis-mouse (mouse model for infammatory bowel disease), alleviated laminarin-induced arthritis in the SKG mouse (model for human rheumatoid arthritis), LPS shock (model for a cytokine storm), and LPS-induced pulmonary infammation (model for COVID-19) suggested that 2-DG is efective for the treatment of various infammatory disease due to its capability to inhibit cytokine receptor glycosylation [28]. accumulation of 2-DG-6-P in cells inhibits phosphoglucose isomerase (PGI) activity.…”