Prostaglandins as endogenous mediators of interleukin 1 production.
We examined the role of cyclooxygenase (CO)-derived metabolites of arachidonic acid (AA) in the regulation of interleukin 1 (IL 1) production by lipopolysaccharide (LPS)-stimulated murine resident peritoneal macrophages. The use of LPS proved to be an efficacious probe, because it stimulated both IL 1 production and AA metabolism via only the CO pathway. The production of the CO metabolites prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2; measured as its stable metabolite 6-Keto prostaglandin F1 alpha) by LPS-stimulated macrophages was demonstrated by high pressure liquid chromatography and radioimmunoassay. The addition of exogenous PGE2 or PGI2 resulted in a dose-dependent suppression of macrophage IL 1 production. Inhibitors of the CO pathway (indomethacin, piroxicam, and ibuprofen) caused a dose-dependent augmentation in the LPS-induced IL 1 response. This augmentation directly correlated with the efficacy of the compounds as CO inhibitors. Similar results were found when macrophage-derived fibroblast growth factor was assessed. The addition of exogenous IL 1 to macrophage cultures caused an increase in the levels of PGE2, over a narrow dose range (0.05 to 0.6 IL 1 units). These studies provide detailed evidence that AA metabolites synthesized via the CO pathway can modulate the production of growth factors by LPS-stimulated macrophages. In addition, our data support the concept that IL 1, as with classical hormones, can regulate its own production through a self-induced inhibitor, PGE2.
Kunkel
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Chensue
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Phan
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D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D015237:Dinoprost; D015232:Dinoprostone; D011464:Epoprostenol / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000502:physiology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D011453:Prostaglandins / Q000502:physiology*; D011458:Prostaglandins E / Q000096:biosynthesis / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011453:Prostaglandins; D011458:Prostaglandins E; D011460:Prostaglandins F; D016718:Arachidonic Acid; D005346:Fibroblast Growth Factors; D015237:Dinoprost; D011464:Epoprostenol; D015232:Dinoprostone; D007213:Indomethacin