Abstract
Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria)-mediated production of cytokines (IL-6, TNF-α, MCP-1, etc) in Raw264.7 cells, primary macrophages, dendritic cells and human monocytes. MCL plays an anti-inflammatory role by inhibiting LPS-induced activation of NF-κB and PI3K/Akt/p70S6K pathways. It has negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. In the acute peritonitis mouse model, MCL reduced the secretion of IL-6, TNF-α, IL-1β, MCP-1, IFN-β and IL-10 in sera, and ameliorated lung and liver damage. MCL down-regulated the high mortality rate caused by lethal LPS challenge. Collectively, our data illustrated that MCL enabled maintenance of immune equilibrium may represent a potentially new anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock.
Highlights
Toll/IL-1 receptor-domain-containing adaptor protein inducing interferon β (IFN-β) (TRIF) is a downstream adaptor of Toll-like receptor 4 (TLR4), which is associated with TANK-binding kinase 1 (TBK1) and activates IFN regulatory factor 3 (IRF3), accounting for type I IFN expression
We demonstrated that the natural product MCL decreased lipopolysaccharide (LPS)-mediated production of IL-6, tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), interferon β (IFN-β ) and IL-10 in Raw264.7, primary peritoneal macrophages, dendritic cells, human monocytic cell THP-1 and human CD14+ monocytes
In order to determine the cytotoxicity of MCL, we first determined the apoptotic sensitivity of Raw264.7 to MCL
Summary
Toll/IL-1 receptor-domain-containing adaptor protein inducing IFN-β (TRIF) is a downstream adaptor of TLR4, which is associated with TANK-binding kinase 1 (TBK1) and activates IFN regulatory factor 3 (IRF3), accounting for type I IFN expression. Phosphatidylinositol (PI) 3-kinase (PI3K) signaling pathway contributes to TLR4-activated immune responses, promoting IL-10 but inhibiting IL-12 expression in immune cells[13]. Sesquiterpene lactones (SLs) are a class of naturally occurring plant terpenoids belonging to Asteraceae family, many of which exhibit diverse biological activities (e.g. antimalarial, anticancer, antiviral, antibacterial, antifungal and anti-inflammatory)[15,16,17]. MCL protects mice from LPS-induced organ damage and high mortality. MCL maintains immune equilibrium by down-regulating proinflammatory cytokines, chemokines, and type I interferon secretion in TLR4 signaling, and attenuate host damage and reduce mortality. MCL is a drug candidate for the development of novel potential immunosuppressive and anti-inflammatory agents for the treatment of septic shock triggered by lethal LPS challenge
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