| 摘要: | ABSTRACT—Lipoteichoic acid (LTA), a gram-positive bacterial outer membrane component, can cause septic shock. Our
previous studies showed that ketamine has anti-inflammatory and antioxidant effects on gram-negative LPS-induced
macrophage activation. In this study, we further evaluated the effects of ketamine on the regulation of LTA-induced TNF-!
and IL-6 gene expressions and oxidative stress production in macrophages and its possible mechanisms. Exposure of
macrophages to a therapeutic concentration of ketamine (100 2M) inhibited LTA-induced TNF-! and IL-6 expressions at
protein or mRNA levels. In parallel, ketamine at 100 2M reduced LTA-stimulated phosphorylation of extracellular
signalYregulated kinase 1/2 (ERK1/2). Sequentially, ketamine reduced the LTA-triggered translocation of nuclear factor-.B
(NF.B) from the cytoplasm to nuclei and its transactivation activity. Pretreatment with PD98059, an inhibitor of ERK,
decreased LTA-enhanced NF.B activation and TNF-! and IL-6 mRNA syntheses. Cotreatment with ketamine
and PD98059 synergistically suppressed the LTA-induced translocation and transactivation of NF.B and biosyntheses
of TNF-! and IL-6 mRNA. Application of toll-like receptor 2 (TLR2) small interfering RNA (si)RNA into macrophages
decreased the levels of this receptor, and simultaneously ameliorated LTA-augmented NF.B transactivation and
consequent production of TNF-! and IL-6 mRNA. Cotreatment with ketamine and TLR2 siRNA synergistically lowered
TNF-! and IL-6 mRNA syntheses in LTA-activated macrophages. Ketamine and TLR2 siRNA could reduce the LTAinduced
increases in production of nitrite and intracellular reactive oxygen species in macrophages, and their combination
had better effects than a single exposure. Thus, this study shows that one possible mechanism involved in ketamineinduced
inhibition of LTA-induced TNF-! and IL-6 gene expressions and oxidative stress production is through
downregulating TLR2-mediated phosphorylation of ERK1/2 and the subsequent translocation and transactivation of NF.B.
KEYWORDS—Ketamine, macrophages, LTA, TLR2, inflammatory cytokines, oxidative stress |
