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.
- Copyright © 1986 by American Association of Immunologists