Propofol suppresses tumor necrosis factor-alpha biosynthesis in lipopolysaccharide-stimulated macrophages possibly through downregulation of nuclear factor-kappa B-mediated toll-like receptor 4 gene expression.
Lipopolysaccharide (LPS), a gram-negative bacterial outer membrane component, can activate macrophages via a toll-like receptor 4-dependent pathway. Our previous study has shown that propofol, an intravenous anesthetic reagent, has anti-inflammatory effects. This study was further aimed to evaluate the roles of toll-like receptor 4 in propofol-caused suppression of tumor necrosis factor-alpha (TNF-alpha) biosynthesis in LPS-stimulated macrophages and its possible molecular mechanisms. Exposure of macrophages to propofol and LPS did not affect cell viability. Meanwhile, the LPS-caused augmentations in the productions of TNF-alpha protein and mRNA were significantly decreased following incubation with a therapeutic concentration of propofol (50 microM). Analysis of toll-like receptor 4 small interference (si)RNA revealed that this membrane receptor might participate in the propofol-caused suppression of TNF-alpha biosynthesis. Treatment of macrophages with LPS-induced toll-like receptor 4 protein and mRNA productions. Propofol at a clinically relevant concentration could inhibit such induction. In parallel, the LPS-induced translocation and transactivation of transcription factor nuclear factor-kappa B (NFkappaB) were significantly alleviated following propofol incubation. There are several NFkappaB DNA-binding motifs found in the promoter region of toll-like receptor 4. Therefore, this study shows that propofol at a therapeutic concentration can downregulate TNF-alpha biosynthesis possibly via inhibition of NFkappaB-mediated toll-like receptor 4 gene expression.
Wu
Gong-Jhe
GJ
Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Chen
Ta-Liang
TL
Chang
Chia-Chen
CC
Chen
Ruei-Ming
RM
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015742:Propofol / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D015742:Propofol