Lipoteichoic acid-induced tnf-α and il-6 gene expressions and oxidative stress production in macrophages are suppressed by ketamine through downregulating toll-like receptor 2-mediated activation of erk1/2 and nfκb

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50 引文 斯高帕斯(Scopus)

摘要

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-α 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 μM) inhibited LTA-induced TNF-α and IL-6 expressions at protein or mRNA levels. In parallel, ketamine at 100 μM reduced LTA-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Sequentially, ketamine reduced the LTA-triggered translocation of nuclear factor-κB (NFκB) from the cytoplasm to nuclei and its transactivation activity. Pretreatment with PD98059, an inhibitor of ERK, decreased LTA-enhanced NFκB activation and TNF-α and IL-6 mRNA syntheses. Cotreatment with ketamine and PD98059 synergistically suppressed the LTA-induced translocation and transactivation of NFκB and biosyntheses of TNF-α 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 NFκB transactivation and consequent production of TNF-α and IL-6 mRNA. Cotreatment with ketamine and TLR2 siRNA synergistically lowered TNF-α and IL-6 mRNA syntheses in LTA-activated macrophages. Ketamine and TLR2 siRNA could reduce the LTA-induced 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 ketamine-induced inhibition of LTA-induced TNF-α 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 NFκB.
原文英語
頁(從 - 到)485-492
頁數8
期刊Shock
33
發行號5
DOIs
出版狀態已發佈 - 5月 2010

ASJC Scopus subject areas

  • 重症監護和重症監護醫學
  • 急診醫學
  • 醫藥 (全部)

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