Platelet-activating factor antagonists suppress the generation of tumor necrosis factor-alpha and superoxide induced by lipopolysaccharide or phorbol ester in rat liver macrophages.
Platelet-activating factor (PAF) has been shown to play an important role in the generation of tumor necrosis factor-alpha (TNF-alpha) and superoxide in guinea pig peritoneal macrophages. In this study, the effects of the PAF receptor antagonists, WEB 2170 and RP 59277, and of a PAF analogue, HAGPT, on TNF-alpha and superoxide production by rat Kupffer cells was investigated. The liver macrophages produced very little TNF-alpha and superoxide when exposed to PAF, but released substantial amounts of superoxide following treatment with zymosan or phorbol 12-myristate 13-acetate (PMA). WEB 2170 not only inhibited the generation of superoxide by PMA but also suppressed the LPS-induced TNF-alpha synthesis by Kupffer cells in a concentration-dependent manner. Northern blot analysis revealed that the expression of TNF-alpha mRNA induced by lipopolysaccharide (LPS) in Kupffer cells was partially abrogated by WEB 2170 or RP 59227. Furthermore, WEB 2170 reduced the PMA-induced leakage of lactate dehydrogenase (LDH) from Kupffer cells in a dose-dependent manner. These data suggest that TNF-alpha and superoxide syntheses in Kupffer cells are rather insensitive to exogenous PAF. On the other hand, the PAF antagonists used in this study interfere with the transduction of the signals induced by LPS, PMA or zymosan. It is questionable whether the PAF receptor of the plasma membrane is involved in the inflammatory response of rat Kupffer cells.
Zhang
F
F
Biochemisches Institut, Albert-Ludwigs-Universitat, Freiburg, Germany.
Decker
K
K
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D001381:Azepines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C063964:bepafant; D013755:Tetradecanoylphorbol Acetate