Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition.
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.
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China.
Wangsheng
W
Wang
Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Chunming
C
Guo
Department of Obstetrics and Gynecology, No. 401 Hospital, Qingdao 266100, P. R. China.
Ping
P
Zhu
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China.
Jiangwen
J
Lu
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China.
Wenjiao
W
Li
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China.
Chao
C
Liu
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China.
Huiliang
H
Xie
Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Leslie
L
Myatt
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China.
Zi-Jiang
ZJ
Chen
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P. R. China. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, P. R. China. sungangrenji@hotmail.com.
Kang
K
Sun
D000650:Amnion / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D036801:Parturition / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D006854:Hydrocortisone