Stimulation of prostaglandin (PG) F2 alpha and PGE2 release by tumour necrosis factor-alpha and interleukin-1 alpha in cultured human luteal phase endometrial cells

Abstract

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) are important mediators of cell signalling in the uterus. Prostaglandins (PG) have been implicated in the increase of endometrial vascular permeability which occurs during the implantation process. This study evaluates the effect of these two pleiotropic cytokines on PGF2 alpha and PGE2 release from human luteal phase endometrial glandular epithelial cells (GEC) and stromal cells (STC) in culture. Basal PGF and PGE release did not differ significantly from each other or among cell types, and declined significantly with increasing number of days in culture. On day 3, basal PG release had decreased to half of that on day 1 of culture. However, both cell types were still able to respond to the addition of exogenous arachidonic acid (5 microM) on day 3 of culture, with PG release by GEC being elevated 7- to 10-fold and by STC moderately, but still significantly, on day 4. The permissive effect of arachidonic acid on the stimulation of PG release may indicate the down-regulation of phospholipase A2 with continued time in culture. However, the addition of arachidonic acid (5 microM) on day 0 of culture, while able to cause significantly increased PG release from GEC, had no effect on STC. In contrast, the addition of a combination of arachidonic acid (5 microM), and either recombinant human TNF-alpha (10 micrograms rhTNF-alpha/l) or 10 micrograms rhIL-1 alpha/l, had a synergistic action and caused the significantly increased release of PGF and PGE from both cell types, compared with that achieved with either arachidonic acid or the cytokine alone (although GEC responded more than STC). During the first 24 h after the addition of rhTNF-alpha or rhIL-1 alpha, both cytokines stimulated PG release from both cell types in a dose- and time-dependent fashion. Neither cycloheximide (10 microM) nor actinomycin D (10 microM) affected basal PG release, but both blocked cytokine-induced PG release from both cell types. These results suggest that there is a differential control of human endometrial cell PG biosynthesis, and that PG release may be regulated through gene activation.