Regulation by prostaglandin E2 of cytokine-elicited nitric oxide synthesis in rat liver macrophages.
Nitric oxide (NO), apart from its properties as a vasodilator, is a cytotoxic agent released from macrophages upon stimulation with immunomodulating agents such as interferon-gamma and endotoxin. In rat Kupffer cells endotoxin causes the release of NO as well as of tumor necrosis factor-alpha and prostaglandin E2 (PGE2). This eicosanoid and its second messenger, cyclic AMP, have been shown to increase nitric oxide formation in Kupffer cells treated with endotoxin (Gaillard et al. (1991) Pathobiology 59, 280-283). But not only added PGE2 but also the prostaglandin produced endogenously upon stimulation with endotoxin increases NO synthesis. Neither tumor necrosis factor-alpha nor interleukin-1 beta stimulate NO synthesis by themselves, but together with PGE2 they are as effective as lipopolysaccharide plus PGE2. To replace PGE2 in the combination with the cytokines, however, dibutyryl cAMP has to be present in higher concentrations than with LPS. Interleukin-6 alone or in combination with PGE2 or dibutyryl cAMP is without any effect. Anti-TNF-alpha as well as anti-PGE2 antibodies reduce the release of NO upon stimulation with LPS. Consequently, the effect of LPS on NO production seems to be in part due to the self-stimulating effect of PGE2 and some cytokines, both produced by Kupffer cells upon LPS stimulation.
Gaillard
T
T
Biochemisches Institut, Universität Freiburg, Germany.
Mülsch
A
A
Klein
H
H
Decker
K
K
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000502:physiology; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003994:Bucladesine; D000242:Cyclic AMP; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate