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Wu H.-X.,Fudan University | Guo P.-F.,Fudan University | Jin L.-P.,Fudan University | Liang S.-S.,Fudan University | And 2 more authors.
Human Reproduction | Year: 2010

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a novel cytokine that triggers the dendritic cell-mediated TH2 response and regulatory T cell expansion. The aim of this study is to evaluate whether TSLP and TSLP receptor (TSLPR) are expressed in primary human extravillous trophoblast (EVT), how proimflammatory cytokines (tumor necrosis factor (TNF)-, IL-1), TH2 and TH3 cytokines (IL-4, TGF-) and pregnancy-associated hormones regulate TSLP production by EVT and whether the SLP-TSLPR interaction affects the biological behavior of trophoblsts.METHODSWe assessed TSLP mRNA and protein expression by real-time RT-PCR, ELISA and immunochemistry, respectively. We further investigated effects of TSLP on the proliferation and invasion of trophoblast cells in vitro.RESULTS:The primary EVTs constitutively expressed TSLP and TSLPR. IL-4 and TNF-or pregnancy-associated hormones result in a significant increase in TSLP mRNA expression and protein release from EVT, and TSLP promotes primary EVT proliferation and invasion in vitro.CONCLUSIONSThis study has demonstrated that the first-trimester human trophoblast cells express TSLP and TSLPR, that cytokine milieu which mimics the maternal-fetal interface modulates expression of TSLP in trophoblast and that TSLP stimulates trophoblast proliferation and invasion. This suggests that TSLP plays an important role in human EVT invasion and placentation in human early pregnancy. © 2010 The Author.


Du M.R.,Fudan University | Zhou W.H.,Fudan University | Zhou W.H.,Wuhan University | Piao H.L.,Fudan University | And 4 more authors.
Human Reproduction | Year: 2012

Background Our previous studies have demonstrated that cyclosporin A (CsA) can increase the cell number in and invasion by human first-trimester trophoblasts and induce maternalfetal tolerance. C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine ligand 12 (CXCL12) are important mediators at the maternalfetal interface during early pregnancy. In this study, we further investigate the molecular mechanisms underlying modulation by CsA of the crosstalk between human cytotrophoblast and decidual stromal cell (DSC). Methods Human first-trimester cytotropoblast and DSC were treated with CsA in the absence or presence of U0126 pretreatment, and then the mRNA and protein levels of CXCL12 and CXCR4 were measured by RTPCR, qPCR, in-cell western blots and enzyme-linked immunosorbent assay (ELISA), respectively. 3-(4,5-dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide and Matrigel invasion assays were used to determine the invasiveness of cytotrophoblast, respectively. The activity of matrix metalloproteinase (MMP)-9 and MMP-2 was detected by gelatin zymography. A co-culture with direct contact between cytotrophoblast and DSC was established and used to investigate the interaction between these two cells. Results CsA up-regulated CXCL12 and CXCR4 expression in human first-trimester cytotrophoblast cells, but not in DSCs. Blocking the mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK1/2) signaling by U0126 abrogated the CsA-induced increase in CXCL12 and CXCR4 expression and neutralizing antibodies to CXCL12 or CXCR4 completely inhibited the CsA-induced increase in cell number, invasion and MMP-9 and MMP-2 activity of cytotrophoblast. CsA also significantly promoted the activity of MMP-9 and MMP-2 in DSCs, but this was unaffected by CXCL12 or CXCR4 neutralizing antibody. Furthermore, the CsA-induced MMP-9 and MMP-2 activity and the invasiveness of cytotrophoblast in the cytotrophoblast and DSC co-culture were significantly increased compared with CsA-treated trophoblast cultured alone, and CXCR4 blocking antibody effectively abolished the increased MMP activity and invasion of cytotrophoblasts in the cytotrophoblast-DSC co-culture stimulated by CsA. Conclusions CsA can promote the crosstalk between cytotrophoblast and DSC through up-regulating CXCL12/CXCR4 interaction via MAPK signaling, resulting in the increased numbers of and invasion by human cytotrophoblast cells. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Wu H.-X.,Fudan University | Wu H.-X.,Tongji University | Jin L.-P.,Fudan University | Xu B.,Fudan University | And 3 more authors.
Cellular and Molecular Immunology | Year: 2014

T helper 17 (Th17) cells have both regulatory and protective roles in physiological conditions. The Th17 subset and the cytokine interleukin-17A (IL-17A) have been implicated in the pathogenesis of certain autoimmune diseases, several types of cancer and allograft rejection. However, the role of Th17 cells at the maternal/fetal interface remains unknown. Here, we demonstrate that Th17 cells are present in decidua and are increased in the peripheral blood of 10 clinically normal pregnancies based on intracellular cytokine analysis. Our results suggest a potential role of Th17 cells in sustaining pregnancy in humans. Furthermore, we demonstrate that decidual stromal cells (DSCs) but not trophoblast cells recruit peripheral Th17 cells into the decidua by secreting CCL2. The recruited Th17 cells promote proliferation and invasion and inhibit the apoptosis of human trophoblast cells by secreting IL-17 during the first trimester of pregnancy. These findings indicate a novel role for Th17 cells in controlling the maternal-fetal relationship and placenta development. © 2014 CSI and USTC.


Jin L.-P.,Fudan University | Fan D.-X.,Fudan University | Zhang T.,Fudan University | Guo P.-F.,Fudan University | And 2 more authors.
American Journal of Reproductive Immunology | Year: 2011

To evaluate whether the association of the costimulatory signal regulation with T helper 1/T helper 2 (Th1/Th2) bias at maternal-fetal interface in human pregnancy loss. Method of study The expression of CD80 and CD86 in decidual tissues and CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the decidual T cells was compared between normal early pregnancy and miscarriage by qPCR and Western blot. The cytokine production in decidual T cells was performed by flow cytometry. The correlation of costimulatory molecule expression with Th1/Th2 cytokines was analyzed. Results The CD80 mRNA and protein expression showed no significant difference between normal pregnancy and miscarriage. An increase in the expression of CD28 and CD86 was accompanied by a decrease in the expression of CTLA-4 in miscarriage in comparison with the early pregnancy. The higher expression of interleukin (IL)-2 and interferon-γ (IFN-γ), and lower expression of IL-4 and IL-10 in the decidual T cells were present in miscarriage. A correlation analysis showed a significant positive correlation of CD86 and CD28 expression with the Th1 cytokine production (IL-2 and IFN-γ), a significant negative correlation of CTLA-4 expression with the Th1 cytokine production. Conclusion The upregualtion of costimulatory signals on T cells might form an abnormal immune microenvironment, a shift to Th1 responses, at maternal-fetal interface, which leads to human miscarriage. © 2011 John Wiley & Sons A/S.


Jin L.-P.,Fudan University | Fan D.-X.,Fudan University | Li D.-J.,Fudan University | Li D.-J.,Hainan Medical College Affiliated Hospital
American Journal of Reproductive Immunology | Year: 2011

A pregnancy is associated with modifications in the immune status of the mother, but the mechanisms are not well understood. Several observations have indicated that CD28/CTLA-4 and B7-1/B7-2 are involved in the maternal-fetal immune regulation. This review aims to recapitulate our current knowledge concerning the role of CD28/CTLA-4 and B7-1/B7-2 in maternal-fetal immune regulation.Several studies suggest that up-regulation of B7-2 and/or CD28 and/or down-regulation of CTLA-4 are correlated with the occurrence of pregnancy loss. Therefore, an accurate expression of costimulatory molecules at the maternal-fetal interface may ensure that the decidual cells do not elicit a 'danger' signal to the maternal immune system, perhaps instead contributing to the establishment of immune tolerance in vivo. It is showed that costimulation blockade with anti-B7 mAbs results in altered allogeneic T-cell response and overcomes increased maternal rejection to the fetus, which improves fetus growth in the abortion-prone system. These findings suggest that the anti-B7-treated T cells not only function as potent suppresser cells but also exert immunoregulatory effect on the maternal T cells. This procedure might be potentially useful to immunotherapy for human recurrent spontaneous abortion. © 2011 John Wiley & Sons A/S.


Yan Q.F.,Hainan Medical College Affiliated Hospital
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology | Year: 2012

To investigate the protective effect of luteolin on isolated rat heart in hypothermic preservation. Forty male SD rats were randomly divided into 4 groups (n = 10): control group, luteolin low-dose group (7.5 micromol/L), middle-dose group (15 micromol/L) and high dose group (30 micromol/L). Langendorff model of isolated rat heart was used. After 30 min basal perfusion, the hearts were stored in University of Wisconsin solution (UW solution) at 4 degrees C with luteolin (7.5, 15 and 30 micromol/L) or without luteolin for 12 h and followed by 60 min reperfusion. The recovery of cardiac contractile and diastolic function, coronary flow (CF), creatine kinase (CK) leakage in the coronary effluent, myocardial water content were determined. The myocardial ultrastructure was also observed. The results revealed that luteolin improved the recovery of left ventricular peak systolic pressure and +/- dp/dtmax dose-dependently and increased coronary flow. The leakage of creatine kinase in the coronary effluent was significantly reduced in luteolin-added hearts. Impairment of myocardial ultrastructure after 12 h hypothermic preservation was obviously alleviated in hearts luteolin-added group compared with that in control group. There were no differences between the groups in myocardial water contents. Luteolin as a supplementation in cardiac preservation solution can significantly improve the hypothermic preservation effects on rat heart and have myocardial protection effect, especially in luteolin-added with 30 micromol/L.


Wang X.-Q.,Fudan University | Yu J.,Fudan University | Luo X.-Z.,Fudan University | Shi Y.-L.,Fudan University | And 4 more authors.
Journal of Molecular Endocrinology | Year: 2010

RANTES (C-C chemokine, regulated on activation, normal T cell expressed and secreted) is involved in progression of endometriosis, but the precise mechanism is understood inadequately. This study is to elucidate the roles of RANTES in macrophage recruitment and tolerance in the endometriotic milieu. The expression of RANTES was analyzed by immunohistochemistry. The cell co-cultures were applied to simulate the endometriotic milieu to investigate the regulation of RANTES secretion and its receptor CCR1 expression. Transwell migration assay was used for chemotaxis of U937 cells (macrophage line) to endometrial stromal cells (ESCs) and/or human pelvic mesothelial cells. The expression of CCR1 was analyzed by RT-PCR and qPCR in transcription and by western blot in translation respectively. Concentrations of RANTES, IL10, and IL12p70 were determined by ELISA. The phenotype of U937 cells and apoptosis of ESCs were analyzed by flow cytometry. We have found that the expression of RANTES is significantly higher in the endometriotic tissue and eutopic endometrium than that of the normal endometrium without endometriosis. The combination of 17β-estradiol and dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin increases significantly RANTES secretion in the endometriosis-associated cell co-culture which can recruit more macrophages, upregulate CCR1 expression, and induce tolerant phenotype, which inhibits the apoptosis of ESC in the milieu. In conclusion, the higher levels of RANTES in the ectopic milieu facilitate the onset and progression of endometriosis by macrophage recruitment and tolerance that in turn inhibits apoptosis and enhances growth of ESC. © 2010 Society for Endocrinology.


Quan M.,Shanghai JiaoTong University | Quan M.,University of Houston | Cui J.,Shanghai JiaoTong University | Cui J.,University of Houston | And 8 more authors.
Cancer Research | Year: 2015

Merlin, the protein encoded by the NF2gene, is a memberof the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer. © 2015 AACR.


Guo P.-F.,Fudan University | Du M.-R.,Fudan University | Wu H.-X.,Fudan University | Lin Y.,Shanghai JiaoTong University | And 3 more authors.
Blood | Year: 2010

Thymic stromal lymphopoietins (TSLPs) play critical roles in dendritic cell-mediated immune responses. In this study, we found that human trophoblasts and decidual epithelial cells in maternal-fetal interface of early placentas express TSLP mRNA and protein, but only trophoblast cells secret soluble TSLP. Human decidual CD1c+ DCs (dDCs) highly express the functional TSLP receptor complex TSLP receptor and interleukin-7 receptor-α. Recombinant human TSLP activates CD1C+ decidual DCs and peripheral monocyte-derived DCs with increased costimulatory molecules, major histocompatibility complex class II, and OX-40L. Human TSLP or supernatants from human trophoblasts specifically stimulate dDCs to highly produce interleukin-10 and TH2-attracting chemokine CCL-17. The TSLP-activated dDCs prime decidual CD4+ T cells for TH2 cell differentiation, involved in maternal-fetal immunotolerance. Interestingly, the protein expression of TSLP in normal pregnancy with significant TH2 bias is much higher than that of miscarriage showing TH1 bias at the maternal-fetal interface. Therefore, human trophoblasts may contribute to maternal-fetal tolerance by instructing dDCs to induce regulatory TH2 bias in human early pregnancy via TSLP. © 2010 by The American Society of Hematology.


Piao H.-L.,Fudan University | Wang S.-C.,Fudan University | Tao Y.,Fudan University | Zhu R.,Fudan University | And 5 more authors.
PLoS ONE | Year: 2012

Our previous study has demonstrated that cyclosporine A (CsA) administration in vivo induces Th2 bias at the maternal-fetal interface, leading to improved murine pregnancy outcomes. Here, we investigated how CsA treatment in vitro induced Th2 bias at the human maternal-fetal interface in early pregnancy. The cell co-culture in vitro in different combination of component cells at the maternal-fetal interface was established to investigate the regulation of CsA on cytokine production from the interaction of these cells. It was found that interferon (IFN)-γ was produced only by decidual immune cells (DICs), and not by trophoblasts or decidual stromal cells (DSCs); all these cells secreted interleukin (IL)-4, IL-10, and tumor necrosis factor (TNF)-α. Treatment with CsA completely blocked IFN-γ production in DICs and inhibited TNF-α production in all examined cells. CsA increased IL-10 and IL-4 production in trophoblasts co-cultured with DSCs and DICs although CsA treatment did not affect IL-10 or IL-4 production in any of the cells when cultured alone. These results suggest that CsA promotes Th2 bias at the maternal-fetal interface by increasing Th2-type cytokine production in trophoblasts with the aid of DSCs and DICs, while inhibiting Th1-type cytokine production in DICs and TNF-α production in all investigated cells. Our study might be useful in clinical therapeutics for spontaneous pregnancy wastage and other pregnancy complications. © 2012 Piao et al.

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