scholarly journals The Role of Interleukin-11 in Pregnancy Involves Up-Regulation of α2-Macroglobulin Gene through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 Pathway in the Decidua

2006 ◽  
Vol 20 (12) ◽  
pp. 3240-3250 ◽  
Author(s):  
Lei Bao ◽  
Sangeeta Devi ◽  
Jennifer Bowen-Shauver ◽  
Susan Ferguson-Gottschall ◽  
Lorraine Robb ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Janus Kinase ◽  
Abnormal Development ◽  
Trophoblast Invasion ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Double Mutation ◽  
Α2 Macroglobulin ◽  
Decidual Cells ◽  
In Pregnancy

Abstract IL-11 expressed by endometrial stromal cells is crucial for normal pregnancy. IL-11 receptor α (IL-11Rα) null mice are infertile due to abnormal development of the placenta. In these mice, the mesometrial decidual tissue, which is the site of trophoblast invasion, thins and disappears at mid-pregnancy. Degeneration of the decidua is accompanied by uncontrolled trophoblast invasion. In this report, we show, using IL-11Rα null mice, that a defect in IL-11 signaling in the decidua leads to severe down-regulation of α2-macroglobulin (α2-MG), a metalloproteinase inhibitor crucial for limiting trophoblast invasion. We also present evidence, using uterine stromal cells that decidualize in culture, that IL-11 robustly stimulates the endogenous α2-MG expression and enhances α2-MG promoter activity. Serial 5′ deletion and internal deletion of the promoter reveal two important signal transducer and activator of transcription (Stat) binding sites. Mutation of either one of these motifs decreases IL-11 stimulation, whereas double mutation prevents IL-11 action. We also found that IL-11 activates Janus kinase 2 (Jak2) and induces rapid phosphorylation, nuclear translocation, and promoter binding activity of Stat3 in decidual cells, whereas Jak1, Tyk2, and Stat5 activities are not affected. In addition, Jak2 inhibitor totally prevents α2-MG expression in decidual cells. Taken together, results of this investigation provide, at least in part, an explanation for the overinvasiveness of the trophoblast in IL-11Rα null mice and reveal, for the first time, that IL-11 signals through the Jak2/Stat3 pathway in decidual cells to stimulate the expression of α2-MG, a protease inhibitor essential for normal placentation in pregnancy.

scholarly journals Expression of Functional Prolactin Receptors in Nonpregnant Human Endometrium: Janus Kinase-2, Signal Transducer and Activator of Transcription-1 (STAT1), and STAT5 Proteins Are Phosphorylated after Stimulation with Prolactin

1998 ◽  
Vol 83 (7) ◽  
pp. 2545-2553 ◽  
Author(s):  
H. N. Jabbour ◽  
H. O. D. Critchley ◽  
S. C. Boddy
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Human Endometrium ◽  
Janus Kinase ◽  
Glandular Epithelium ◽  
Ribonuclease Protection Assay ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Secretory Phase ◽  
Stat Proteins

PRL is synthesized by decidualized endometrial stromal cells from the midsecretory phase in a nonconception cycle and throughout pregnancy. The exact role of PRL in the human endometrium remains to be elucidated; however, the pattern of expression supports a role for PRL during implantation and placentation. This study investigated the site and pattern of expression of PRL receptors in the nonpregnant human endometrium. In situ hybridization and immunohistochemistry localized expression of the receptor in the glandular epithelium and a subset of stromal cells of the endometrium. As judged by the intensity of staining, expression of the receptor was dramatically up-regulated during the secretory phase. Expression of the PRL receptor gene in the endometrium from the secretory phase of the menstrual cycle was confirmed by ribonuclease protection assay using 50μ g total ribonucleic acid. Phosphorylation of Janus kinase-2 (JAK2), STAT1 (signal transducer and activator of transcription-1), and STAT5 proteins in response to PRL was investigated to establish the signaling pathway of PRL in the human endometrium. Endometrial tissue was collected during the secretory phase of the menstrual cycle and incubated in the presence of 100 ng/mL human PRL for 0, 5, 10, and 20 min. JAK2 phosphorylation was induced by PRL at 5 min, whereas STAT1 and STAT5 phosphorylation was apparent 20 min after stimulation with PRL. Immunohistochemistry localized the JAK/STAT proteins in the glandular epithelial cells and a subset of stromal cells, as was observed for the PRL receptor. Secretory phase stromal and glandular cells cultured separately and in the presence or absence of 100 ng/mL PRL confirmed the PRL-induced phosphorylation of JAK2/STAT proteins, at least in the glandular compartment. These studies demonstrate an up-regulation of expression of functional PRL receptors during the secretory phase of the menstrual cycle. Further, decidual PRL through a paracrine mechanism may influence glandular epithelial function/secretions and direct gene transcription through the JAK/STAT pathway. The target genes activated by PRL in the glandular epithelium of the nonpregnant human endometrium remain to be elucidated.

scholarly journals Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2883-2893 ◽  
Author(s):  
Joanne Muter ◽  
Paul J. Brighton ◽  
Emma S. Lucas ◽  
Lauren Lacey ◽  
Anatoly Shmygol ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Stromal Cells ◽  
Nuclear Translocation ◽  
Scaffold Protein ◽  
Trophoblast Invasion ◽  
Differentiation Markers ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Phosphoinositide 3 Kinase ◽  
Inactive Protein

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca2+ release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.

scholarly journals Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0180785 ◽  
Author(s):  
Takahiro Sawada ◽  
Daiki Arai ◽  
Xuefeng Jing ◽  
Masayasu Miyajima ◽  
Stuart J. Frank ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Molecular Interactions ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Janus Kinase 2

scholarly journals Decidual PTEN expression is required for trophoblast invasion in the mouse

2010 ◽  
Vol 299 (6) ◽  
pp. E936-E946 ◽  
Author(s):  
Marie-Noëlle Laguë ◽  
Jacqui Detmar ◽  
Marilène Paquet ◽  
Alexandre Boyer ◽  
JoAnne S. Richards ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Giant Cells ◽  
Pten Expression ◽  
Abnormal Development ◽  
Trophoblast Invasion ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Fetal Mortality ◽  
Altered Expression ◽  
Decidual Cells

Trophoblast invasion likely depends on complex cross talk between the fetal and maternal tissues and may involve the modulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling activity in maternal decidual cells. In this report, we studied implantation in Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ mice, which lack the PI3K signaling antagonist gene Pten in myometrial and stromal/decidual cells. Primiparous Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ mice were found to be subfertile because of increased fetal mortality at e11.5. Histopathological analyses revealed a failure of decidual regression in these mice, accompanied by reduced or absent invasion of fetal trophoblast glycogen cells and giant cells, abnormal development of the placental labyrinth, and frequent apparent intrauterine fetal growth restriction. Unexpectedly, the loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN) expression in Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ decidual cells was not accompanied by a detectable increase in AKT phosphorylation or altered expression or activation of PI3K/AKT downstream effectors such as mammalian target of rapamycin or glycogen synthase kinase-3β. Terminal deoxynucleotidyl transferase-mediated nick end labeling and bromodeoxyuridine incorporation analyses attributed to the lack of decidual regression mainly to decreased apoptosis in Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ decidual cells, rather than to increased proliferation. Remodeling of the maternal vasculature was delayed in Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ uteri at e11.5, as evidenced by persistence of vascular smooth muscle and decreased infiltration of uterine natural killer cells. In addition, thickening of the myometrium and disorganization of the muscle fibers were observed before and throughout gestation. Almost all Ptentm1Hwu/tm1Hwu ;Amhr2tm3(cre)Bhr/+ mice failed to carry a second litter to term, apparently attributable to endometrial hyperplasia and uterine infections. Together, these data demonstrate novel roles of PTEN in the mammalian uterus and its requirement for proper trophoblast invasion and decidual regression.

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