Propofol pretreatment attenuates LPS-induced granulocyte-macrophage colony-stimulating factor production in cultured hepatocytes by suppressing MAPK/ERK activity and NF-kappaB translocation.

Abstract

Propofol (PPF), a widely used intravenous anesthetic for induction and maintenance of anesthesia during surgeries, was found to possess suppressive effect on host immunity. This study aimed at investigating whether PPF plays a modulatory role in the lipopolysaccharide (LPS)-induced inflammatory cytokine expression in a cell line of rat hepatocytes. Morphological observation and viability assay showed that PPF exhibits no cytotoxicity at concentrations up to 300 microM after 48 h incubation. Pretreatment with 100 microM PPF for 24 h prior to LPS stimulation was performed to investigate the modulatory effect on LPS-induced inflammatory gene production. The results of semi-quantitative RT-PCR demonstrated that PPF pretreatment significantly suppressed the LPS-induced toll-like receptor (TLR)-4, CD14, tumor necrosis factor (TNF)-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression. Western blotting analysis showed that PPF pretreatment potentiated the LPS-induced TLR-4 downregulation. Flow cytometrical analysis revealed that PPF pretreatment showed no modulatory effect on the LPS-upregulated CD14 expression on hepatocytes. In addition, PPF pretreatment attenuated the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and IkappaBalpha, as well as the nuclear translocation of NF-kappaB primed by LPS. Moreover, addition of PD98059, a MAPK kinase inhibitor, significantly suppressed the LPS-induced NF-kappaB nuclear translocation and GM-CSF production, suggesting that the PPF-attenuated GM-CSF production in hepatocytes may be attributed to its suppressive effect on MAPK/ERK signaling pathway. In conclusion, PPF as an anesthetic may clinically benefit those patients who are vulnerable to sepsis by alleviating sepsis-related inflammatory response in livers.

• Authors: Bruno Jawan, Ying-Hsien Kao, Shigeru Goto, Mei-Chun Pan, Yu-Chun Lin, Li-Wen Hsu, Toshiaki Nakano, Chia-Yun Lai, Cheuk-Kwan Sun, Yu-Fan Cheng, Ming-Hong Tai, Hock-Liew Eng, Chih-Shien Wang, Chia-Jung Huang, Chung-Ren Lin, Chao-Long Chen
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 229 Issue 3 Pg. 362-73 (Jun 15 2008) ISSN: 0041-008X [Print] United States
• PMID: 18387647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Intravenous
• Cytokines
• Lipopolysaccharides
• NF-kappa B
• Granulocyte-Macrophage Colony-Stimulating Factor
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinases
• Propofol

Topics

• Anesthetics, Intravenous (administration & dosage, pharmacology)
• Animals
• Blotting, Western
• Cell Line
• Cell Nucleus (drug effects, metabolism)
• Cytokines (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (drug effects, metabolism)
• Flow Cytometry
• Gene Expression Regulation (drug effects)
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis, drug effects)
• Hepatocytes (drug effects, metabolism)
• Lipopolysaccharides (pharmacology)
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• NF-kappa B (drug effects, metabolism)
• Propofol (administration & dosage, pharmacology)
• Protein Transport
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)