Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y).
All cardinal events during the reproductive cycle, including ovulation, implantation, and menstruation, are characterized by a profound tissue remodeling and an associated local inflammatory response. The ovarian hormone progesterone is a key modulator of inflammatory signals in reproductive tissues, but the underlying mechanisms are not well understood. In this study, we report that differentiating human endometrial stromal cells (ESCs) acquire resistance to interferon-gamma (IFNgamma)-dependent signal transducers and activators of transcription (STAT) 1 signaling, although phosphorylation, nuclear translocation, and binding of STAT1 to DNA, are unaffected. These observations prompted an investigation into the role of nuclear repressors of STAT1 signaling. We demonstrate that protein inhibitor of activated STAT-y is complexed to the progesterone receptor (PR) in human ESCs and that its ability to repress STAT1 signaling is dependent upon activation of PR in response to hormone binding. Conversely, IFNgamma and protein inhibitor of activated STAT-y synergistically inhibited PR-dependent transcription, demonstrating that the progesterone and IFNgamma signaling pathways engage in reciprocal transcriptional antagonism in human endometrium.
Zoumpoulidou
Georgia
G
Institute of Reproductive and Developmental Biology, Wolfson & Weston Research Centre for Family Health, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.
Jones
Marius C
MC
Fernandez de Mattos
Silvia
S
Francis
Julia M
JM
Fusi
Luca
L
Lee
Yun Soo
YS
Christian
Mark
M
Varshochi
Rana
R
Lam
Eric W-F
EW
Brosens
Jan J
JJ
D002454:Cell Differentiation; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000075223:Poly-ADP-Ribose Binding Proteins; D011374:Progesterone / Q000494:pharmacology*; D050828:Protein Inhibitors of Activated STAT; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; C099927:NMI protein, human; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D011980:Receptors, Progesterone; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; C012589:trichostatin A; D011374:Progesterone; D007371:Interferon-gamma; D004247:DNA; D006655:Histone Deacetylases