Prostaglandin E-2-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes

Studies in our laboratory have shown that structural changes in cervical bi opsied fetal membranes, prior to labour, coincide with differences in the e xpression of the gelatinase enzyme, latent matrix metalloproteinase-9 (MMP- 9). Concurrently, in vivo,there is an increase in the expression of prostag landins, notably prostaglandin E-2 (PGE(2)), which has been shown to regula te the expression of MMPs in other systems. The aim of this study was to te st the hypothesis (using an in-vitro culture model) that endogenously produ ced PGE(2) has a role in the elevation of MMP-9 described in vivo. Non-infe cted fetal membranes sampled from women undergoing elective Caesarean secti on were stimulated with 10% (v/v) fetal bovine serum (FBS), a known inducer of prostaglandins. This activation resulted in a time-dependent increase i n the secretion of PGE(2) into the media, as determined by enzyme-linked im munosorbent assay (day 1: 19 +/- 9 pg/ml/24 h to 358 +/- 54 pg/ml/24 h by d ay 4). A similar pattern of secretion of latent MMP-9 was observed in paral lel with the increase in PGE(2) in the same culture media (day 1: 1.63 +/- 0.17 ng/ml/24 h to 4.2 +/- 1.4 ng/ml/24 h by day 4). When both molecules we re compared, a significant (P < 0.01) positive correlation (r = 0.623) was observed. Secretion of the tissue inhibitor of MMPs-9 (TIMP-1) was not sign ificantly different between untreated (3.07 +/- 0.266 <mu>g/ml/24 h) and FB S-treated (3.85 +/- 0.24 mug/ml/24 h) cultures during the first 4 days in c ulture. Prostaglandin synthesis inhibition studies using indomethacin (100 mu mol/l) resulted in a 70-80% reduction in the activated secretion of late nt MHP-9. Direct PGE(2) stimulation of cultures resulted in the bell shaped dose-response curve with concentrations of 1-100 nmol/l (which are within the range secreted in culture in response to FBS), stimulating significant latent MMP-9 secretion. These results suggest a link between endogenous PGE (2) and latent MPP-9 production in human fetal membranes, raising the possi bility that PGE(2) has a role in the mechanism of fetal membrane structural changes and, hence, in parturition-associated membrane rupture.