PROSTAGLANDIN-E2 INHIBITS THE RELEASE OF TUMOR-NECROSIS-FACTOR-ALPHA, RATHER THAN INTERLEUKIN-1-BETA, FROM HUMAN MACROPHAGES

We have reported previously that macrophages obtained from renal patients on continuous ambulatory peritoneal dialysis (CAPD) during an episode of infectious peritonitis display a decrease in intracellular cAMP levels and in spontaneous in vitro release of PGE2 and PGI2. Such macrophages also release large quantities of IL-1-beta and TNF-alpha when stimulated in vitro by LPS. In view of the interregulatory effects between PGE2 and macrophage cytokines (IL-1-beta and TNF-alpha) in their production, we examined in the present work to what extent the LPS-induced release of either IL-1-beta or TNF-alpha in vitro from CAPD-originated peritoneal macrophages is affected by graded doses of exogenous PGE2 (range 0 - 1000 ng/ml) and by the cyclooxygenase inhibitor indomethacin (INDO) (10(-6) M). IL-1-beta and TNF-alpha were determined using an enzyme-linked immunoabsorbent assay and an immunoradiometric assay, respectively. We found that PGE2 invariably induced a dose-dependent decrease in TNF-alpha release. In peritoneal macrophages collected during an infection-free period, TNF-alpha release decreased from 3225 pg/ml (controls) to 353 pg/ml at 1000 ng/ml of PGE2, and in peritoneal macrophages collected during an episode of infectious peritonitis, it decreased from 4100 pg/ml (controls) to 545 pg/ml at 100 ng/ml of PGE2. However, PGE2 failed to influence the secretion of IL-1-beta. INDO induced an approx. two-fold increase in TNF-alpha release, but had no effect on IL-1-beta release. These findings indicate that exogenous and endogenous PGE2 controls the release of TNF-alpha rather than IL-1-beta from LPS-stimulated peritoneal macrophages.