LIPOTEICHOIC ACID-INDUCED TNF-alpha 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 NF kappa B

作者：Chang Huai Chia; Lin Ke Hsun; Tai Yu Ting; Chen Juei Tai; Chen Ruei Ming^*

来源：Shock, 2010, 33(5): 485-492.

DOI：10.1097/SHK.0b013e3181c3cea5

• Ketamine
• macrophages
• LTA
• TLR2
• inflammatory cytokines
• oxidative stress

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-alpha 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 mu M) inhibited LTA-induced TNF-alpha and IL-6 expressions at protein or mRNA levels. In parallel, ketamine at 100 mu M reduced LTA-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Sequentially, ketamine reduced the LTA-triggered translocation of nuclear factor-kappa B (NF kappa B) from the cytoplasm to nuclei and its transactivation activity. Pretreatment with PD98059, an inhibitor of ERK, decreased LTA-enhanced NF kappa B activation and TNF-alpha and IL-6 mRNA syntheses. Cotreatment with ketamine and PD98059 synergistically suppressed the LTA-induced translocation and transactivation of NF kappa B and biosyntheses of TNF-alpha 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 kappa B transactivation and consequent production of TNF-alpha and IL-6 mRNA. Cotreatment with ketamine and TLR2 siRNA synergistically lowered TNF-alpha 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-alpha 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 kappa B.

• 出版日期2010-5
• 单位河北医科大学