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Introduction: In explant cultures of human fetal membranes (FM) granulocyte-macrophage-colony-stimulating-factor (GM-CSF) mediates the inflammation-induced FM weakening seen in preterm premature rupture of the membranes (pPROM) and exogenous progesterone (P4) inhibits GM-CSF and inflammation-induced FM weakening. Here we report that GM-CSF induces P4 production within the FM which then acts in a paracrine manner to counteract GM-CSF-induced weakening.

Methods: FM explants mounted in Transwell inserts were cultured with control media and increasing GM-CSF, RU486 (blocks P4 action), or trilostane (blocks P4 production). P4 production, matrix metalloproteinase-2 (MMP-2) and FM rupture strength were determined. Effects of GM-CSF on P4 production and abundance of the 3ß-hydroxysteroid dehydrogenase (3ßHSD) enzyme in the BeWo human trophoblast cell line were also determined.

Results: GM-CSF induced P4 production in both FM explants and BeWo cells in a concentration-dependent manner. GM-CSF also increased 3βHSD protein in BeWo cells.  Incubation of FMs with RU486, or trilostane, each caused increased FM weakening.  Trilostane also increased MMP-2.  Exogenous P4 with trilostane repressed MMP-2 and restored FM strength.

Conclusion: GM-CSF induced P4 production by FM and trophoblastic cells suggesting that locally produced P4 is increased by factors that weaken FM. Inhibition of local P4 production or action resulted in FM weakening with concomitant MMP-2 induction suggesting local P4 maintains FM structural integrity. This weakening is reversed by exogenous P4. These data are consistent with a negative-feedback system whereby P4 induced by GM-CSF, the mediator of inflammation-induced FM weakening, counteracts GM-CSF, inhibiting both its production and downstream action with resultant preservation of FM structural integrity.