title: Promotion of interferon-gamma production by natural killer cells via suppression of murine peritoneal macrophage prostaglandin E₂ production using intravenous anesthetic propofol.
abstract: Propofol is an intravenous anesthetic, widely used for general anesthesia during surgery, which inevitably involves tissue trauma with inflammation. At sites of inflammation, prostanoids, especially prostaglandin E₂ (PGE₂), are abundant. This study addresses the effect of propofol on macrophage PGE₂ production. Using thioglycollate-elicited murine peritoneal macrophages, propofol (7.5-30 μM) suppressed lipopolysaccharide-induced PGE₂ production. The suppression was via the direct inhibition of cyclooxygenase (COX) enzyme activity and due neither to the downregulation of COX expression nor the inhibition of arachidonic acid release from plasma membranes. In macrophage:natural killer (NK) cell co-culture, propofol dramatically increased interferon-gamma (IFN-γ) production, and the actions of propofol were mimicked by a selective COX-2 inhibitor, NS-398, as well as the selective EP4 receptor antagonist L-161,982, suggesting a role of PGE₂ suppression in the upregulation of IFN-γ production. Furthermore, in purified NK cell culture, PGE₂ directly suppressed the production of IFN-γ by activated NK cells, which was reversed by selective inhibition of EP4 activity. Taken together, our results show that, in macrophage:NK cell co-culture, propofol, through the suppression of macrophage PGE₂ production, upregulates NK cell IFN-γ production by alleviating EP4 receptor-mediated suppression of IFN-γ production. Propofol may potentially exert considerable influence on inflammation and immunity by suppressing PGE₂ synthesis.
authors.affiliation: Department of Anesthesiology, Kansai Medical University, Osaka, Japan. nvkc20988@hera.eonet.ne.jp
authors.forename: Takefumi
authors.initials: T
authors.lastname: Inada
authors.forename: Kozue
authors.initials: K
authors.lastname: Kubo
authors.forename: Koh
authors.initials: K
authors.lastname: Shingu
mesh_terms: D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018686:Anesthetics, Intravenous; D016718:Arachidonic Acid; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D015742:Propofol