anisomycin and Sepsis

Anisomycin is known to inhibit eukaryotic protein synthesis and has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanism of action have not been explained in macrophages. Here, we demonstrated the anti-inflammatory effects of anisomycin both in vivo and in vitro. We found that anisomycin decreased the mortality rate of macrophages in cecal ligation and puncture (CLP)- and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediators such as inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β as well as the nitric oxide and proinflammatory cytokines production in macrophages subjected to LPS-induced acute sepsis. Furthermore, anisomycin attenuated nuclear factor (NF)-κB activation in LPS-induced macrophages, which correlated with the inhibition of phosphorylation of NF-κBinducing kinase and IκB kinase, phosphorylation and IκBα proteolytic degradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammation by inhibiting NF-κB-related inflammatory gene expression and could be a potential therapeutic candidate for sepsis. [BMB Reports 2021; 54(11): 545-550].

Topics: Animals; Anisomycin; Female; Gene Expression Regulation; I-kappa B Proteins; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide; Protein Synthesis Inhibitors; Sepsis

To investigate the molecular mechanism underlying heme oxygenase-1 (HO-1)-modulated infiltration of neutrophils, the sepsis model of cecal ligation and puncture in Sprague-Dawley rats was used. In vivo induction and suppression of HO-1 were performed by pretreatment with cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX, respectively. Tricarbonyldichlororuthenium(II) dimer, [Ru(CO)₃Cl₂]₂ (a carbon monoxide [CO] releaser), and hemoglobin (a CO scavenger) were used to examine the participation of HO-1/CO in the effect of CoPP pretreatment on formylated peptide (fMLP)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Anisomycin (a p38 MAPK activator) and SB203580 (a p38 MAPK inhibitor) were used to examine p38 MAPK mediation in the attenuation of fMLP-attracted migration by HO-1. The results demonstrated that zinc protoporphyrin IX and CoPP pretreatment conferred enhancing and inhibitory effects, respectively, on hepatic neutrophil infiltration. Pretreatment with CoPP inhibited fMLP-induced migration and p38 MAPK phosphorylation in neutrophils ex vivo. The [Ru(CO)₃Cl₂]₂ stimulated whereas hemoglobin diminished the suppression of fMLP-induced p38 MAPK phosphorylation by CoPP. Moreover, anisomycin diminished the suppressive effects of CoPP pretreatment on fMLP-induced migration, actin polymerization, polarization, and migration speed of neutrophils. These results suggest that HO-1 in neutrophil attenuates its infiltration during sepsis via the inactivation of p38 MAPK. Understanding the mechanism that diminishes neutrophil infiltration by HO-1 may help prevent hepatic failure during sepsis.

Topics: Animals; Anisomycin; Blotting, Western; Cell Movement; Enzyme Activation; Heme Oxygenase-1; Liver; Male; Neutrophil Infiltration; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Polymerase Chain Reaction; Protoporphyrins; Rats; Rats, Sprague-Dawley; Sepsis