Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFκB

Wen Ta Chiu, Yi Ling Lin, Chih Wei Chou, Ruei Ming Chen

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33 Citations (Scopus)

Abstract

Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 μM significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. In parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NFκB) from the cytoplasm to nuclei. Propofol at 50 μM decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NFκB. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NFκB.

Original languageEnglish
Pages (from-to)430-439
Number of pages10
JournalChemico-Biological Interactions
Volume181
Issue number3
DOIs
Publication statusPublished - Oct 30 2009
Externally publishedYes

Fingerprint

Toll-Like Receptor 2
NF-kappa B
Macrophages
Propofol
Gene expression
Down-Regulation
Chemical activation
Gene Expression
Phosphorylation
Biosynthesis
Nitrites
Messenger RNA
lipoteichoic acid
Electrophoretic mobility
Gram-Positive Bacteria
Septic Shock
RNA Interference
Reporter Genes
Small Interfering RNA
Transcriptional Activation

Keywords

  • iNOS
  • Lipoteichoic acid
  • Macrophages
  • Propofol
  • Raf-MEK1/2-ERK1/2-IKK-NFκB
  • Toll-like receptor 2

ASJC Scopus subject areas

  • Toxicology

Cite this

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title = "Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFκB",
abstract = "Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 μM significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. In parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NFκB) from the cytoplasm to nuclei. Propofol at 50 μM decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NFκB. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NFκB.",
keywords = "iNOS, Lipoteichoic acid, Macrophages, Propofol, Raf-MEK1/2-ERK1/2-IKK-NFκB, Toll-like receptor 2",
author = "Chiu, {Wen Ta} and Lin, {Yi Ling} and Chou, {Chih Wei} and Chen, {Ruei Ming}",
year = "2009",
month = "10",
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doi = "10.1016/j.cbi.2009.06.011",
language = "English",
volume = "181",
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TY - JOUR

T1 - Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFκB

AU - Chiu, Wen Ta

AU - Lin, Yi Ling

AU - Chou, Chih Wei

AU - Chen, Ruei Ming

PY - 2009/10/30

Y1 - 2009/10/30

N2 - Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 μM significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. In parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NFκB) from the cytoplasm to nuclei. Propofol at 50 μM decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NFκB. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NFκB.

AB - Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 μM significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. In parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NFκB) from the cytoplasm to nuclei. Propofol at 50 μM decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NFκB. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NFκB.

KW - iNOS

KW - Lipoteichoic acid

KW - Macrophages

KW - Propofol

KW - Raf-MEK1/2-ERK1/2-IKK-NFκB

KW - Toll-like receptor 2

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U2 - 10.1016/j.cbi.2009.06.011

DO - 10.1016/j.cbi.2009.06.011

M3 - Article

C2 - 19573522

AN - SCOPUS:70249119956

VL - 181

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JO - Chemico-Biological Interactions

JF - Chemico-Biological Interactions

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