Theissenolactone C inhibits lipopolysaccharide-induced TAK-1/IKK signaling and improves septic injuries in vivo

Sepsis is a common leading cause of death and evolves to multi-organ injury. Clinical studies show that endotoxin lipopolysaccharide (LPS) acts as an exogenous pyrogen and produces many types of mediators involved in septic shock. In vivo and in vitro, LPS can induce the expression of pro-inflammatory mediators in human monocytes, such as proteinases, cytokines and inducible nitric oxide synthase (NOS). The released cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, play important roles in sepsis or chronic infection. These cytokines could also enhance the matrix metalloproteinases (MMP) production in monocytes, which leads to serious tissue structure destruction. Theissenolactone C (LC53) is derived from the Taiwan strains Xylariaceae (Xylariaceae) Theissenia cinerea. In this study, microarray technology was first applied to detect the possible regulated genes in LPS-activated human monocytic cells (THP-1) under pretreatment of LC53. We also found LC53 obviously decreased LPS-induced extracellular MMP-9, TNF-α and IL-6 levels in THP-1 cells within 24 hours. It inhibited LPS-induced intracellular MMP-9 protein and mRNA expression. In signaling studies, LC53 could block the LPS-induced degradation of IκBα, p65 translocation, and NF-κB regulated gene reporter activity. It also decreased the phosphorylation of IKKα/β while not affected the TAK1 and p38 phosphorylation. In vivo studies showed LC53 could improve the cecum shrinkage, decrease plasma TNF-α/IL-6 levels, and lower the hepatic iNOS/MMP-9 expression in LPS-induced mice endotoxemia model. Theissenolactone C may be a promising potential therapeutic agent which might be through its inhibition on TAK1/TAB2/3/IKK pathway for endotoxemia injuries. Three samples of RNA are analyzed. THP-1 cells were stimulated with 50 ng/ml LPS for 8 hours (LPS group). Cells were pretreated with LC53 (5 μM) for 15min and subsequently stimulated with 50 ng/ml LPS for 8 hours (LC53 group). Resting group is untreated anything.