Convergence of Interferon-γ and Progesterone Signaling Pathways in Human Endometrium: Role of PIASy (Protein Inhibitor of Activated Signal Transducer and Activator of Transcription-y)

Abstract

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.

The Interaction of Piasy with Trim32, an E3-Ubiquitin Ligase Mutated in Limb-girdle Muscular Dystrophy Type 2H, Promotes Piasy Degradation and Regulates UVB-induced Keratinocyte Apoptosis through NFκB

“…2A), in agreement with previous reports (2). This was in contrast to Piasy, which, in the absence of treatment, presented predominantly nuclear staining, in agreement with previous observations of endogenous Piasy localization (34) and the general description of PIAS family members such as nuclear proteins (35) These colocalization experiments demonstrate that Piasy and Trim32 can interact in mammalian cells, and suggested Pictures of the plates were taken after 5 days of culture at 30°C. B, summary of the interactions between Trim32 and members of the PIAS family as determined in the yeast two-hybrid assay, using the same methods as in A.…”

“…Nucleocytoplasmic Redistribution of Piasy and Interaction with Trim32 in the Cytoplasm-We and others have reported that Trim32 is localized in cytoplasmic speckles (2,8), whereas Piasy and PIAS family members in general are considered nuclear proteins (34,35). Thus, it was important to determine the subcellular localization of the interaction of Trim32 and Piasy.…”

Heparin inhibits interferon-γ signaling in human endometrial stromal cells by interference with the cellular binding of interferon-γ

“…We have recently reported an inverse regulation of the IFN-g-R and its signaling response through STAT-1 in human ESCs during decidualization (12). In line with these observations, another study observed that decidualizing ESCs acquire a reduced responsiveness to IFN-g due to a convergence of IFN-g and P signaling (13).…”

“…A possible dosedependency or the involvement of other signaling pathways might be an explanation for this observation. Nevertheless, the lack of effects of heparin on Nmi probably does not have many functional consequences as Nmi does not enhance IFN-g-dependent transcription in decidualized ESCs (13).…”

NK Cells Expressing a Progesterone Receptor Are Susceptible to Progesterone-Induced Apoptosis

“…Furthermore, a recent study observed the convergence of IFN-␥ and P4 signaling pathways in endometrial stromal cells and demonstrated that progesterone was able to antagonize the signaling pathways of IFN-␥ (36).…”