Interdependence of tumor necrosis factor, prostaglandin E2, and protein synthesis in lipopolysaccharide-exposed rat Kupffer cells.
Kupffer cells are the main producers of tumor necrosis factor-alpha (TNF; cachectin) and eicosanoids in the liver exposed to lipopolysaccharide (endotoxin; LPS). A very rapid but transient release of TNF is followed by a slow, steady synthesis of prostaglandin E2 (PGE2). TNF itself is able to provoke eicosanoid synthesis in Kupffer cells; the rate and pattern of prostaglandin production are similar to those observed after treatment with LPS. Anti-TNF antibodies completely neutralize TNF action on Kupffer cells, thus ruling out any participation of contaminating LPS. LPS stimulation of PGE2 production in Kupffer cells is reduced by the antiserum to 50%, indicating an involvement of TNF in the stimulatory action of LPS. On the other hand, PGE2, a potent inhibitor of LPS-elicited TNF release, is able to suppress LPS- but not TNF-stimulated eicosanoid synthesis in rat Kupffer cells. In addition to this autocrine circuit, extrahepatic factors participate in the regulation of Kupffer cell activation: glucocorticoids not only inhibit TNF or prostaglandin production, they also reverse the LPS-specific changes in the prostaglandin pattern of Kupffer cells. LPS, TNF or cycloheximide when given alone in the concentration range applied in this study do not affect the viability of rat Kupffer cells. However, the combinations of cycloheximide and either LPS or TNF cause rapid death of the cultured cells. The cytolytic potential of either combination cannot be alleviated by treatment with glucocorticoids.
Peters
T
T
Biochemisches Institut, Albert-Ludwigs-Universität, Freiburg, Federal Republic of Germany.
Karck
U
U
Decker
K
K
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D007700:Kinetics; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D012475:Salmonella; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D003513:Cycloheximide; D015232:Dinoprostone