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

• Published in: Toxicology and applied pharmacology 2008-06, Vol.229 (3), p.362-373
• Main Authors: Jawan, Bruno, Kao, Ying-Hsien, Goto, Shigeru, Pan, Mei-Chun, Lin, Yu-Chun, Hsu, Li-Wen, Nakano, Toshiaki, Lai, Chia-Yun, Sun, Cheuk-Kwan, Cheng, Yu-Fan, Tai, Ming-Hong, Eng, Hock-Liew, Wang, Chih-Shien, Huang, Chia-Jung, Lin, Chung-Ren, Chen, Chao-Long
• Format: Article
• Language: English
• Subjects: Granulocyte–macrophage colony-stimulating factor; Lipopolysaccharides; Mitogen-activated protein kinases; NF-κB translocation; Toll-like receptor-4
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2008.01.044

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 μM after 48 h incubation. Pretreatment with 100 μM 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)-α, 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 IκBα, as well as the nuclear translocation of NF-κB primed by LPS. Moreover, addition of PD98059, a MAPK kinase inhibitor, significantly suppressed the LPS-induced NF-κB 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.