RESUMEN
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-1ß, 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.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Desoxiglucosa/farmacología , Glicosilación/efectos de los fármacos , Inflamación/prevención & control , Receptores de Citocinas/efectos de los fármacos , Animales , Células Cultivadas , Receptor gp130 de Citocinas/antagonistas & inhibidores , Receptor gp130 de Citocinas/metabolismo , Síndrome de Liberación de Citoquinas/prevención & control , Citocinas/metabolismo , Inflamación/inducido químicamente , Quinasas Janus/efectos de los fármacos , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Citocinas/inmunología , Receptores de Citocinas/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismoRESUMEN
The cytokine storm following sepsis has been proven to be an important mechanism for triggering acute respiratory distress syndrome, which is a fatal uncontrolled systemic inflammation characterized by high concentrations of pro-inflammatory cytokines and chemokines, secreted by immune effector cells. The cytokine storm also occurs in the recently emerged novel coronavirus disease (COVID-19). Therefore, cytokines which usually help the immune system to fight infections are potentially harmful in the course of COVID-19 infections. Therefore, avoiding or mitigating the cytokine storm may be a key treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/sangre , Inmunosupresores/uso terapéutico , Neumonía Viral/patología , Betacoronavirus , COVID-19 , Receptor gp130 de Citocinas/antagonistas & inhibidores , Síndrome de Liberación de Citoquinas/patología , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Pandemias , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/patologíaRESUMEN
COVID-19 is viral respiratory infection with frequently fatal lung complications in the elderly or in people with serious comorbidities. Lung destruction appears to be associated with a cytokine storm related to an increased level of interleukin-6 (IL6). Therapeutic targeting of the interleukin-6 signaling pathway can attenuate such a cytokine storm and can be beneficial for patients with COVID-19 in danger of pulmonary failure. This article demonstrates the importance of IL6 in progression of disease and the possibility of inhibition of IL6 signaling in COVID-19 therapy.