Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1β gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells

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Title:	Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1β gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells
Authors:	陳瑞明 Chen TL;Chang CC;Lin YL;Ueng YF;Chen RM
Contributors:	醫學科學研究所
Date:	2009
Issue Date:	2009-08-25 09:56:30 (UTC+8)
Abstract:	Ketamine may affect the host immunity. Interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) are pivotal cytokines produced by macrophages. This study aimed to evaluate the effects of ketamine on the regulation of inflammatory cytokine gene expression, especially IL-1 beta, in lipopolysaccharide (LPS)-activated murine macrophage-like Raw 264.7 cells and its possible signal-transducing mechanisms. Administration of Raw 264.7 cells with a therapeutic concentration of ketamine (100 microM), LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. Exposure to 100 microM ketamine decreased the binding affinity of LPS and LPS-binding protein but did not affect LPS-induced RNA and protein synthesis of TLR4. Treatment with LPS significantly increased IL-1 beta, IL-6, and TNF-alpha gene expressions in Raw 264.7 cells. Ketamine at a clinically relevant concentration did not affect the synthesis of these inflammatory cytokines, but significantly decreased LPS-caused increases in these cytokines. Immunoblot analyses, an electrophoretic mobility shift assay, and a reporter luciferase activity assay revealed that ketamine significantly decreased LPS-induced translocation and DNA binding activity of nuclear factor-kappa B (NF kappaB). Administration of LPS sequentially increased the phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK. However, a therapeutic concentration of ketamine alleviated such augmentations. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA reduced cellular TLR4 amounts and ameliorated LPS-induced RAS activation and IL-1 beta synthesis. Co-treatment with ketamine and TLR4 siRNA synergistically ameliorated LPS-caused enhancement of IL-1 beta production. Results of this study show that a therapeutic concentration of ketamine can inhibit gene expression of IL-1 beta possibly through suppressing TLR4-mediated signal-transducing phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK and subsequent translocation and transactivation of NF kappaB.
Relation:	Toxicology and Applied Pharmacology.
Data Type:	article
Appears in Collections:	[Graduate Institute of Medical Sciences] Periodical Article

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