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
- 1 May 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Shock
- Vol. 33 (5), 485-492
- https://doi.org/10.1097/shk.0b013e3181c3cea5
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-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.Keywords
This publication has 40 references indexed in Scilit:
- The clinical role of NMDA receptor antagonists for the treatment of postoperative painBest Practice & Research Clinical Anaesthesiology, 2007
- Ketamine Attenuates Early Lipopolysaccharide-Induced Gastric Dysfunction: Role of Stress-Inducible PhosphoproteinsJournal Of Trauma-Injury Infection and Critical Care, 2007
- Ketamine reduces nitric oxide biosynthesis in human umbilical vein endothelial cells by down-regulating endothelial nitric oxide synthase expression and intracellular calcium levels*Critical Care Medicine, 2005
- Anti‐Inflammatory and Antioxidative Effects of Propofol on Lipopolysaccharide‐Activated MacrophagesAnnals of the New York Academy of Sciences, 2005
- HEMODYNAMIC AND IMMUNE CONSEQUENCES OF OPIATE ANALGESIA AFTER TRAUMA/HEMORRHAGEShock, 2004
- Ketamine significantly reduces the migration of leukocytes through endothelial cell monolayersCritical Care Medicine, 1998
- Anaesthetic agents decrease the activity of nitric oxide synthase from human polymorphonuclear leucocytesBritish Journal of Anaesthesia, 1995
- Inhibition of phagocytosis and killing of bacteria by anaesthetic agents in vitroBritish Journal of Anaesthesia, 1995
- Ketamine: an update on the first twenty-five years of clinical experienceCanadian Journal of Anesthesia/Journal canadien d'anesthésie, 1989
- Ketamine—Its Pharmacology and Therapeutic UsesAnesthesiology, 1982