Saikosaponin a protects against experimental sepsis via inhibition of NOD2-mediated NF-κB activation

Abstract

The excessive production of inflammatory cytokines during invasive infection primarily mediates the pathophysiology of sepsis. To improve the survival of septic patients, many selective or mediator-specific anti-inflammatory agents have been developed. Saikosaponin A (SsA), a triterpenoid saponin isolated from Radix Bupleuri, inhibits the production of proinflammatory mediators in several cell types and protects against CCl 4 -induced liver injury in rats. However, whether SsA treatment provides protective effects against sepsis remains unknown. The aim of the present study was to investigate the anti-inflammatory role of SsA in septic rats and the possible involvement of the nucleotide-binding oligomerization domain 2 (NOD2)/NF-κB signaling pathway in the regulation of inflammatory cytokine expression. Sixty male Wistar rats were randomly divided into six groups (10 rats per group): Sham surgery, cecal ligation and puncture (CLP), CLP plus SsA (1.0 mg/kg), CLP plus SsA (2.5 mg/kg), CLP plus SsA (5.0 mg/ kg) and sham surgery plus SsA (2.5 mg/kg) groups. Rats in the SsA groups were intraperitoneally (i.p.) injected with different doses of SsA following the CLP surgery. Tissues from the ileum were harvested 8 h after CLP or sham surgery and the levels of inflammatory cytokines and NOD2 mRNA, and the activation of NF-κB were measured. The concentrations of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as the NOD2 mRNA expression levels and NF-κB activation in the intestinal tissues were significantly increased in the septic rats of the CLP group compared with those in the sham group. SsA administration effectively suppressed the increase in the levels of TNF-α and IL-6. Moreover, the upregulation of NOD2 mRNA expression and phospho-NF-κB p65 levels was significantly inhibited following the administration of SsA. SsA may exert a protective role in the septic process by suppressing TNF-α and IL-6 concentrations in the intestines of septic rats and these effects appear to be mediated, at least partly, via inhibition of the NOD2/NF-κB signaling pathway.