REGULATED EXPRESSION OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2 BY UTERINE STROMA

Our previous studies demonstrated that interleukin-1 alpha (IL-1 alpha ) and soluble factors secreted by polarized uterine luminal epithelial cells (UEC) stimulate prostaglandin (PG) secretion by uterine stromal cells (USC). The present studies were aimed at determining the mechan ism by which these agonists stimulate PG secretion by USC. The complet e inhibition of IL-1 alpha- and UEC-induced PGE(2) secretion by cycloh eximide and actinomycin-D in the presence of a saturating concentratio n of arachidonic acid indicated that IL-1 alpha and UEC act to a large extent by inducing de novo expression of PG endoperoxide synthase (PG HS). Western blot analysis of membrane fractions from USC showed a 2- to 4-fold accumulation of the mitogen-inducible isoform of PGHS (PGHS- 2), but not the constitutively expressed enzyme (PGHS-1), within 3 h o f treatment with IL-1 alpha, UEC-conditioned medium, or serum. Inhibit ion of UEC-stimulated PGHS-2 expression by anti-IL-1 alpha indicated t hat IL-1 alpha is one factor secreted by UEC responsible for the synth esis of USC PGHS-2. Expression of PGHS-2, but not PGHS-1, was inhibite d by dexamethasone. Dexamethasone also inhibited IL-1 alpha- and UEC-s timulated PGE(2) secretion by USC. Immunohistochemical studies demonst rated that PGHS-2 is localized to implantation sites in newly differen tiating USC at the time of blastocyst attachment, indicating a potenti al physiological role for PGHS-2 in early stages of mouse implantation . In contrast, PGHS-1 was localized to UEC during this period. Collect ively, these results indicate that enhanced PG secretion by USC in res ponse to IL-1 alpha and soluble factors secreted by UEC is due to sele ctive expression of PGHS-2. In addition, the expression of PGHS-2 by U SC in vivo during the periimplantation period may support PG secretion required during early stages of embryo implantation.