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Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation.
Toxicol Appl Pharmacol. 2008 Apr 01; 228(1):105-13.TA

Abstract

Our previous study showed that ketamine, an intravenous anesthetic agent, has anti-inflammatory effects. In this study, we further evaluated the effects of ketamine on the regulation of tumor necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6) gene expressions and its possible signal-transducing mechanisms in lipopolysaccharide (LPS)-activated macrophages. Exposure of macrophages to 1, 10, and 100 microM ketamine, 100 ng/ml LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. A concentration of 1000 microM of ketamine alone or in combined treatment with LPS caused significant cell death. Administration of LPS increased cellular TNF-alpha and IL-6 protein levels in concentration- and time-dependent manners. Meanwhile, treatment with ketamine concentration- and time-dependently alleviated the enhanced effects. LPS induced TNF-alpha and IL-6 mRNA syntheses. Administration of ketamine at a therapeutic concentration (100 microM) significantly inhibited LPS-induced TNF-alpha and IL-6 mRNA expressions. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA into macrophages decreased cellular TLR4 levels. Co-treatment of macrophages with ketamine and TLR4 siRNA decreased the LPS-induced TNF-alpha and IL-6 productions more than alone administration of TLR4 siRNA. LPS stimulated phosphorylation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos from the cytoplasm to nuclei. However, administration of ketamine significantly decreased LPS-induced activation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos. LPS increased the binding of nuclear extracts to activator protein-1 consensus DNA oligonucleotides. Administration of ketamine significantly ameliorated LPS-induced DNA binding activity of activator protein-1. Therefore, a clinically relevant concentration of ketamine can inhibit TNF-alpha and IL-6 gene expressions in LPS-activated macrophages. The suppressive mechanisms occur through suppression of TLR4-mediated sequential activations of c-Jun N-terminal kinase and activator protein-1.

Authors+Show Affiliations

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18191973

Citation

Wu, Gone-Jhe, et al. "Ketamine Inhibits Tumor Necrosis Factor-alpha and Interleukin-6 Gene Expressions in Lipopolysaccharide-stimulated Macrophages Through Suppression of Toll-like Receptor 4-mediated c-Jun N-terminal Kinase Phosphorylation and Activator Protein-1 Activation." Toxicology and Applied Pharmacology, vol. 228, no. 1, 2008, pp. 105-13.
Wu GJ, Chen TL, Ueng YF, et al. Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation. Toxicol Appl Pharmacol. 2008;228(1):105-13.
Wu, G. J., Chen, T. L., Ueng, Y. F., & Chen, R. M. (2008). Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation. Toxicology and Applied Pharmacology, 228(1), 105-13. https://doi.org/10.1016/j.taap.2007.11.027
Wu GJ, et al. Ketamine Inhibits Tumor Necrosis Factor-alpha and Interleukin-6 Gene Expressions in Lipopolysaccharide-stimulated Macrophages Through Suppression of Toll-like Receptor 4-mediated c-Jun N-terminal Kinase Phosphorylation and Activator Protein-1 Activation. Toxicol Appl Pharmacol. 2008 Apr 1;228(1):105-13. PubMed PMID: 18191973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation. AU - Wu,Gone-Jhe, AU - Chen,Ta-Liang, AU - Ueng,Yune-Fang, AU - Chen,Ruei-Ming, Y1 - 2007/12/08/ PY - 2007/10/09/received PY - 2007/11/16/revised PY - 2007/11/28/accepted PY - 2008/1/15/pubmed PY - 2008/4/29/medline PY - 2008/1/15/entrez SP - 105 EP - 13 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 228 IS - 1 N2 - Our previous study showed that ketamine, an intravenous anesthetic agent, has anti-inflammatory effects. In this study, we further evaluated the effects of ketamine on the regulation of tumor necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6) gene expressions and its possible signal-transducing mechanisms in lipopolysaccharide (LPS)-activated macrophages. Exposure of macrophages to 1, 10, and 100 microM ketamine, 100 ng/ml LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. A concentration of 1000 microM of ketamine alone or in combined treatment with LPS caused significant cell death. Administration of LPS increased cellular TNF-alpha and IL-6 protein levels in concentration- and time-dependent manners. Meanwhile, treatment with ketamine concentration- and time-dependently alleviated the enhanced effects. LPS induced TNF-alpha and IL-6 mRNA syntheses. Administration of ketamine at a therapeutic concentration (100 microM) significantly inhibited LPS-induced TNF-alpha and IL-6 mRNA expressions. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA into macrophages decreased cellular TLR4 levels. Co-treatment of macrophages with ketamine and TLR4 siRNA decreased the LPS-induced TNF-alpha and IL-6 productions more than alone administration of TLR4 siRNA. LPS stimulated phosphorylation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos from the cytoplasm to nuclei. However, administration of ketamine significantly decreased LPS-induced activation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos. LPS increased the binding of nuclear extracts to activator protein-1 consensus DNA oligonucleotides. Administration of ketamine significantly ameliorated LPS-induced DNA binding activity of activator protein-1. Therefore, a clinically relevant concentration of ketamine can inhibit TNF-alpha and IL-6 gene expressions in LPS-activated macrophages. The suppressive mechanisms occur through suppression of TLR4-mediated sequential activations of c-Jun N-terminal kinase and activator protein-1. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/18191973/Ketamine_inhibits_tumor_necrosis_factor_alpha_and_interleukin_6_gene_expressions_in_lipopolysaccharide_stimulated_macrophages_through_suppression_of_toll_like_receptor_4_mediated_c_Jun_N_terminal_kinase_phosphorylation_and_activator_protein_1_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(07)00549-2 DB - PRIME DP - Unbound Medicine ER -