Abstract
Excessive inflammation associated with the uncontrolled release of pro-inflammatory cytokines is the main cause of death from influenza virus infection. Previous studies have indicated that inhibition of interferon gamma-induced protein 10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), or their cognate receptors has beneficial effects. Here, by using monocytic U937 cells that capable of secreting the three important cytokines during influenza A virus infection, we measured the inhibitory activities on the production of three cytokines of six anti-inflammatory compounds reported in other models of inflammation. We found that ponatinib had a highly inhibitory effect on the production of all three cytokines. We tested ponatinib in a mouse influenza model to assess its therapeutic effects with different doses and administration times and found that the delayed administration of ponatinib was protective against lethal influenza A virus infection without reducing virus titers. Therefore, we suggest that ponatinib may serve as a new immunomodulator in the treatment of influenza.
Highlights
Influenza has attracted extensive attention due to its remarkably high mortality and morbidity with 650,000 deaths worldwide associated with seasonal influenza-caused respiratory diseases [1]
Ponatinib was identified to have inhibitory activity on the production of IL8, induced protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1) in U937 cells infected by H1N1 influenza virus PR8 strain (Figure 1, Table 1)
It has been reported that human primary monocytes and derived macrophages and dendritic cells can be infected with influenza viruses and release large amounts of cytokines [25,26,27]
Summary
Influenza has attracted extensive attention due to its remarkably high mortality and morbidity with 650,000 deaths worldwide associated with seasonal influenza-caused respiratory diseases [1]. A major cause of patient death from influenza is acute respiratory distress syndrome, which is caused by excessive inflammation in the lung [4]. Therapies that suppress exaggerated inflammatory responses and immune-mediated pulmonary injury could be effective at reducing the mortality and morbidity from influenza. There have been no effective immunomodulatory agents available for treating severe influenza, because classical anti-inflammatory drugs, such as corticosteroids, have been reported to worsen patient outcomes in the clinic. Novel drugs aiming to suppress the inflammation induced by influenza are urgently needed [5, 6]
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