Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present.
Lipopolysaccharide (LPS) is the primary mediator of Gram-negative
sepsis by inducing the production of macrophage-derived proinflammatory
cytokines, in which activation of
nuclear factor-kappaB (
NF-kappaB) plays an important role.
PC-SPES is an eight-herb mixture active against a variety of
malignancies, including
prostate cancer and
leukemia. In this study, we demonstrated that
PC-SPES inhibited the LPS-induced
NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that
PC-SPES inhibited the binding of
NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of
NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced
mitogen-activated
protein (MAP)
kinase signaling;
PC-SPES did not affect LPS-induced phosphorylation of MAP
kinases, including c-Jun NH2-terminal
kinase, p38, and
extracellular signal-regulated kinase 1/2. Moreover,
PC-SPES decreased the production of proinflammatory
cytokines and inducible
enzymes, such as
tumor necrosis factor (
TNF) alpha,
interleukin (IL)-1beta,
IL-6,
cyclooxygenase-2, as well as
inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and
interferon-gamma. Furthermore,
PC-SPES rescued C57BL/6 mice from death caused by LPS-induced
septic shock in conjunction with decreased serum levels of
TNFalpha and IL-1beta. Together,
PC-SPES is a potent inhibitor of
NF-kappaB and might be useful for the treatment of
sepsis and inflammatory diseases.