Inhibition of toll-like receptor-4, nuclear factor-κB and mitogen-activated protein kinase by lignocaine may involve voltage-sensitive sodium channels

Ping Ying Lee, Pei-Shan Tsai, Ya Hsien Huang, Chun Jen Huang

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

1. We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-κB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 μmol/L), LPS + tetrodotoxin (TTX; 1 μmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 μmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3. We found that LPS significantly increased the concentrations of TLR-4, NF-κB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-κB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-κB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.

Original languageEnglish
Pages (from-to)1052-1058
Number of pages7
JournalClinical and Experimental Pharmacology and Physiology
Volume35
Issue number9
DOIs
Publication statusPublished - Sep 2008

Fingerprint

Toll-Like Receptor 4
Sodium Channels
Lidocaine
Mitogen-Activated Protein Kinases
Veratridine
Phosphotransferases
Macrophages
p38 Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Sodium Channel Agonists
Sodium Channel Blockers
JNK Mitogen-Activated Protein Kinases
Tetrodotoxin
Enzymes
Endotoxins
Lipopolysaccharides
Sepsis
Up-Regulation
Cell Culture Techniques

Keywords

  • Lignocaine
  • Mitogen-activated protein kinases
  • Nuclear factor-κB
  • Sodium channel
  • Toll-like receptor

ASJC Scopus subject areas

  • Physiology
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

@article{c7ede3877f8e491abe40700bae0b6681,
title = "Inhibition of toll-like receptor-4, nuclear factor-κB and mitogen-activated protein kinase by lignocaine may involve voltage-sensitive sodium channels",
abstract = "1. We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-κB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 μmol/L), LPS + tetrodotoxin (TTX; 1 μmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 μmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3. We found that LPS significantly increased the concentrations of TLR-4, NF-κB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-κB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-κB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.",
keywords = "Lignocaine, Mitogen-activated protein kinases, Nuclear factor-κB, Sodium channel, Toll-like receptor",
author = "Lee, {Ping Ying} and Pei-Shan Tsai and Huang, {Ya Hsien} and Huang, {Chun Jen}",
year = "2008",
month = "9",
doi = "10.1111/j.1440-1681.2008.04962.x",
language = "English",
volume = "35",
pages = "1052--1058",
journal = "Clinical and Experimental Pharmacology and Physiology",
issn = "0305-1870",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - Inhibition of toll-like receptor-4, nuclear factor-κB and mitogen-activated protein kinase by lignocaine may involve voltage-sensitive sodium channels

AU - Lee, Ping Ying

AU - Tsai, Pei-Shan

AU - Huang, Ya Hsien

AU - Huang, Chun Jen

PY - 2008/9

Y1 - 2008/9

N2 - 1. We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-κB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 μmol/L), LPS + tetrodotoxin (TTX; 1 μmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 μmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3. We found that LPS significantly increased the concentrations of TLR-4, NF-κB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-κB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-κB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.

AB - 1. We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-κB and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 μmol/L), LPS + tetrodotoxin (TTX; 1 μmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 μmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3. We found that LPS significantly increased the concentrations of TLR-4, NF-κB and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-κB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-κB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.

KW - Lignocaine

KW - Mitogen-activated protein kinases

KW - Nuclear factor-κB

KW - Sodium channel

KW - Toll-like receptor

UR - http://www.scopus.com/inward/record.url?scp=48749125890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48749125890&partnerID=8YFLogxK

U2 - 10.1111/j.1440-1681.2008.04962.x

DO - 10.1111/j.1440-1681.2008.04962.x

M3 - Article

C2 - 18505446

AN - SCOPUS:48749125890

VL - 35

SP - 1052

EP - 1058

JO - Clinical and Experimental Pharmacology and Physiology

JF - Clinical and Experimental Pharmacology and Physiology

SN - 0305-1870

IS - 9

ER -