Inhibition of toll-like receptor-4, nuclear factor-kappaB and mitogen-activated protein kinase by lignocaine may involve voltage-sensitive sodium channels.
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)-kappaB 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. Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 micromol/L), LPS + tetrodotoxin (TTX; 1 micromol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 micromol/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. We found that LPS significantly increased the concentrations of TLR-4, NF-kappaB 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-kappaB, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-kappaB and MAPKs in activated macrophages. Moreover, these effects involve VSSC.
Lee
Ping-Ying
PY
Department of Cardiology Mackay Memorial Hospital, Taipei, Taiwan.
Tsai
Pei-Shan
PS
Huang
Ya-Hsien
YH
Huang
Chun-Jen
CJ
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
D000779:Anesthetics, Local; D008070:Lipopolysaccharides; D016328:NF-kappa B; D015222:Sodium Channels; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D013779:Tetrodotoxin; D008012:Lidocaine; D020928:Mitogen-Activated Protein Kinases