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

Wangsheng Wang, Chunming Guo, Ping Zhu, Jiangwen Lu, Wenjiao Li, Chao Liu, Huiliang Xie, Leslie Myatt, Zi Jiang Chen, Kang Sun

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberRA106
JournalScience Signaling
Volume8
Issue number400
DOIs
StatePublished - Oct 27 2015
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Phosphorylation
Amnion
Cyclooxygenase 2
Hydrocortisone
Dinoprostone
Parturition
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Fibroblasts
Tissue
Gene encoding
Glucocorticoid Receptors
Personnel
Prostaglandins
Receptors, Prostaglandin E, EP4 Subtype
Chemical activation
Prostaglandin Receptors
Cyclic AMP Response Element-Binding Protein
Response Elements

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition. / Wang, Wangsheng; Guo, Chunming; Zhu, Ping; Lu, Jiangwen; Li, Wenjiao; Liu, Chao; Xie, Huiliang; Myatt, Leslie; Chen, Zi Jiang; Sun, Kang.

In: Science Signaling, Vol. 8, No. 400, RA106, 27.10.2015.

Research output: Contribution to journalArticle

Wang, Wangsheng ; Guo, Chunming ; Zhu, Ping ; Lu, Jiangwen ; Li, Wenjiao ; Liu, Chao ; Xie, Huiliang ; Myatt, Leslie ; Chen, Zi Jiang ; Sun, Kang. / Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition. In: Science Signaling. 2015 ; Vol. 8, No. 400.
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abstract = "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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