Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression
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Anisomycin is known to inhibit eukaryotic protein synthesisand has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanismof action have not been explained in macrophages. Here,we demonstrated the anti-inflammatory effects of anisomycinboth in vivo and in vitro. We found that anisomycin decreasedthe mortality rate of macrophages in cecal ligation and puncture(CLP)- and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediatorssuch as inducible nitric oxide synthase, tumor necrosisfactor-α, and interleukin-1β as well as the nitric oxide and proinflammatorycytokines production in macrophages subjectedto LPS-induced acute sepsis. Furthermore, anisomycin attenuatednuclear factor (NF)-κB activation in LPS-induced macrophages,which correlated with the inhibition of phosphorylation of NF-κBinducingkinase and IκB kinase, phosphorylation and IκBα proteolyticdegradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammationby inhibiting NF-κB-related inflammatory gene expressionand could be a potential therapeutic candidate for sepsis.
Abstract
Anisomycin is known to inhibit eukaryotic protein synthesisand has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanismof action have not been explained in macrophages. Here,we demonstrated the anti-inflammatory effects of anisomycinboth in vivo and in vitro. We found that anisomycin decreasedthe mortality rate of macrophages in cecal ligation and puncture(CLP)- and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediatorssuch as inducible nitric oxide synthase, tumor necrosisfactor-α, and interleukin-1β as well as the nitric oxide and proinflammatorycytokines production in macrophages subjectedto LPS-induced acute sepsis. Furthermore, anisomycin attenuatednuclear factor (NF)-κB activation in LPS-induced macrophages,which correlated with the inhibition of phosphorylation of NF-κBinducingkinase and IκB kinase, phosphorylation and IκBα proteolyticdegradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammationby inhibiting NF-κB-related inflammatory gene expressionand could be a potential therapeutic candidate for sepsis.
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