Research ArticleReproductive Biology

Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition

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Sci. Signal.  27 Oct 2015:
Vol. 8, Issue 400, pp. ra106
DOI: 10.1126/scisignal.aac6151

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Labor, STAT!

The glucocorticoid cortisol has anti-inflammatory effects in many tissues of the body. However, in fetal membranes during labor, cortisol is associated with increased activity of the inflammatory enzyme COX-2, which produces prostaglandins that promote reproductive smooth muscle changes in the mother that enable delivery. Using primary human amnion fibroblasts from full-term births from patients who delivered after active labor or through nonlabor cesarean sections, Wang et al. found that the interaction of the glucocorticoid receptor and the transcription factor STAT3 at the gene encoding COX-2 mediates an autocrine feed-forward loop that amplifies cortisol-triggered prostaglandin production. The findings identify a mechanism linking cortisol to inflammatory prostaglandin production in the amnion.


The induction of cyclooxygenase-2 (COX-2) and subsequent production of prostaglandin E2 (PGE2) by cortisol in the amnion contrast with the effect of cortisol on most other tissues, but this proinflammatory effect of cortisol may be a key event in human parturition (labor). We evaluated the underlying mechanism activated by cortisol in primary human amnion fibroblasts. Exposure of the amnion fibroblasts to cortisol led to the activation of the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) pathway, which induced the phosphorylation of the kinase SRC and STAT3 (signal transducer and activator of transcription 3). STAT3 interacted with the glucocorticoid receptor (GR) and the transcription factor CREB-1 (cAMP response element–binding protein 1) at the promoter of the gene encoding COX-2, which promoted the production of the secreted prostaglandin PGE2. PGE2 activates the prostaglandin receptors EP2 and EP4, which stimulate cAMP-PKA signaling. Thus, cortisol reinforced the activation of cAMP-PKA signaling through an SRC–STAT3–COX-2–PGE2–mediated feedback loop. Inhibiting STAT3, SRC, or the cAMP-PKA pathway attenuated the cortisol-stimulated induction of COX-2 and PGE2 production in amnion fibroblasts. In human amnion tissue, the amount of phosphorylated STAT3 correlated positively with that of cortisol, COX-2, and PGE2, and all were more abundant in tissue obtained after active labor than in tissue obtained from cesarean surgeries in the absence of labor. These results indicated that the coordinated recruitment of STAT3, CREB-1, and GR to the promoter of the gene encoding COX-2 contributes to the feed-forward induction of COX-2 activity and prostaglandin synthesis in the amnion during parturition.

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