During the coronavirus disease(COVID-19)epidemic,there have been concerns about the impact of vaccines on people’s fertility,including the fertility of those who are currently preparing for pregnancy and those who mi...During the coronavirus disease(COVID-19)epidemic,there have been concerns about the impact of vaccines on people’s fertility,including the fertility of those who are currently preparing for pregnancy and those who might become pregnant in future.However,there is still a lack of research on the effect of the COVID-19 vaccine on male fertility,and it is not surprising that couples and donors have concerns regarding vaccination.In this study,a retrospective cohort study was conducted to examine semen quality before and after receipt of the inactivated COVID-19 vaccine.There were no statistically significant changes in semen parameters(volume,sperm concentration,progressive motility,and total progressive motile count)after two doses of vaccine(all P>0.05).In summary,our study updates the most recent studies on the effects of the COVID-19 vaccine on male fertility,and the information from this study could be used to guide fertility recommendations for assisted reproductive technology(ART)patients and donors.展开更多
Objective:To observe the effects of Ginger moxibustion combined with iontophoresis with traditional Chinese medicine on the improvement of symptoms, serum platelet activating factor (PAF) level and uterine artery puls...Objective:To observe the effects of Ginger moxibustion combined with iontophoresis with traditional Chinese medicine on the improvement of symptoms, serum platelet activating factor (PAF) level and uterine artery pulsation index in patients with primary dysmenorrhea.Methods 114 patients with primary dysmenorrhea who were treated in our hospital from August 2017 to February 2019 were divided into two groups according to the different treatment schemes. 57 patients in the control group were treated with ibuprofen capsules, and 57 patients in the study group were treated with Ginger moxibustion combined with iontophoresis with traditional Chinese medicine. After three menstrual cycles of treatment, the curative effect was evaluated and the improvement of symptoms was counted. PAF, PAF-AH and platelet adhesion rate were compared, uterine artery hemodynamics was measured, and levels of serum hs-CRP and IL-6 were measured.Results The overall response rate of the study group was significantly higher than that of the control group (P < 0.05). After treatment, the scores of different symptoms in the two groups were significantly lower than those before treatment (P < 0.05), and the scores of different symptoms in the study group were significantly lower than those in the control group (P < 0.05). After treatment, PAF and platelet adhesion rate in the two groups were significantly lower than those before treatment (P < 0.05), PAF-AH was significantly higher than that before treatment (P < 0.05), and PAF and platelet adhesion rate in the study group were significantly lower than those in the control group (P < 0.05), PAF-AH was significantly higher than that in the control group (P < 0.05). After treatment, the pulsation index, resistance index and peak systolic-diastolic ratio in the study group were significantly lower than those before treatment (P < 0.05), and the pulsation index, resistance index and peak systolic-diastolic ratio in the study group were significantly lower than those in the control group (P < 0.05). After treatment, the levels of serum hs-CRP and IL-6 in the two groups were significantly lower than those before treatment (P < 0.05), and the levels of serum hs-CRP and IL-6 in the study group were significantly lower than those in the control group (P < 0.05).Conclusions Ginger moxibustion combined with iontophoresis with traditional Chinese medicine is helpful to improve the overall response rate of primary dysmenorrhea treatment, reduce the score levels of different symptoms, rationally improve PAF, PAF-AH, platelet adhesion rate, and the pulse index, resistance index, peak systolic-diastolic ratio are decreased significantly, and serum hs-CRP and IL-6 levels tend to be normal.展开更多
Macrophages are crucial for a successful pregnancy, and malfunctions of decidual macrophages correlate with adverse pregnancyoutcomes, such as spontaneous abortion and preeclampsia. Previously, decidual macrophages we...Macrophages are crucial for a successful pregnancy, and malfunctions of decidual macrophages correlate with adverse pregnancyoutcomes, such as spontaneous abortion and preeclampsia. Previously, decidual macrophages were often thought to be a singlepopulation. In the present study, we identified three decidual macrophage subsets, CCR2−CD11cLO (CD11clow, ~80%), CCR2−CD11cHI (CD11chigh, ~5%), and CCR2+CD11cHI (CD11chigh, 10–15%), during the first trimester of human pregnancy by flowcytometry analysis. CCR2−CD11cLO macrophages are widely distributed in the decidua, while CCR2−CD11cHI and CCR2+CD11cHImacrophages are primarily detected close to extravillous trophoblast cells according to immunofluorescence staining. According toRNA sequencing bioinformatics analysis and in vitro functional studies, these three subsets of macrophages have differentphagocytic capacities. CCR2+CD11cHI macrophages have pro-inflammatory characteristics, while the CCR2−CD11cHI population issuggested to be anti-oxidative and anti-inflammatory due to its high expression of critical heme metabolism-related genes,suggesting that these two subsets of macrophages maintain an inflammatory balance at the leading edge of trophoblast invasionto facilitate the clearance of pathogen infection as well as maintain the homeostasis of the maternal-fetal interface. The presentstudy physiologically identifies three decidual macrophage subsets. Further clarification of the functions of these subsets willimprove our understanding of maternal-fetal crosstalk in the maintenance of a healthy pregnancy.展开更多
Objective:Female reproductive aging is characterized by reduced responsiveness of the hypothalamus to E2-positive feedback,which can result in alterations of gene expression and luteinizing hormone(LH)surge dysfunctio...Objective:Female reproductive aging is characterized by reduced responsiveness of the hypothalamus to E2-positive feedback,which can result in alterations of gene expression and luteinizing hormone(LH)surge dysfunction.We hypothesize that age-related changes in E2-responsive gene expression are due to altered histone acetylation by histone deacetylases(HDACs)or estrogen receptor-alpha(ERα)coactivators with histone acetyltransferase(HAT)activity.Methods:In the present study,young and middle-aged female rats were ovariectomized(OVX)and treated with E2 or oil once per day for 2 days.At the time of the expected LH surge,the anterior and posterior hypothalami were dissected,and gene expression of 11 HDACs and 4 ERαcoactivators with HAT activity was measured using real-time polymerase chain reaction.Results:In the anterior hypothalamus,age affected the gene expression of 3 HDACs(Hdac3,Hdac5,and Hdac11)and 2 ERαcoactivators(Src2 and Crebbp).E2 treatment significantly decreased mRNA levels of 4 HDACs(Hdac4,Hdac5,Hdac10,and Hdac11)and 2 ERαcoactivators(Src2 and Crebbp)in young females(3-4 months).However,none of the genes responded to E2 in the middle-aged females(9-11 months),except Hdac10.In the posterior hypothalamus,age influenced Hdac5 and Src1 mRNA expression.E2 treatment increased Hdac4 and Crebbp mRNA levels in the young but not middle-aged females.Conclusions:These data suggest that E2 regulates HDACs and ERαcoactivators with HAT activity in an age-and E2-dependent manner,which may contribute to the age-related gene expression changes on the day of LH surge in female reproductive aging.展开更多
Objective:Mifepristone(RU486),one of the most common medications for artificial abortion,attenuates the immunoregulatory effects of progesterone.However,the specific immune regulatory mechanism of RU486 in abortion re...Objective:Mifepristone(RU486),one of the most common medications for artificial abortion,attenuates the immunoregulatory effects of progesterone.However,the specific immune regulatory mechanism of RU486 in abortion remains unknown.We intended to investigate the immunomodulatory effects of RU486 on abortion.Methods:Sixty female mice were divided into the control group(0 mg RU486)and RU486 group(2 mg/kg RU486).The uterus,peripheral blood,and spleen were obtained for isolation of specific cell types.The population and phenotype of immune cells in the decidua,peripheral blood,and spleen were analyzed using flow cytometry.Statistical differences between groups were determined using two-tailed t-test.For all statistical tests,P<0.05 was considered statistically significant.Results:RU486 effectively induced abortion in pregnant mice,with a significantly higher number of decidual macrophages(dMφ)(control group=25.55%±2.467%,RU486 group=19.41%±1.423%;P<0.05),especially the major histocompatibility complex II high subset.No difference in Mφnumber was observed in the spleen or peripheral blood.Moreover,the dMφfrom mice with RU486-induced abortion displayed a remarkable activated phenotype,with increased expressions of inducible nitric oxide synthase,tumor necrosis factor-α,and interleukin(IL)-12 but decreased expressions of arginase-1 and IL-10.We also found elevated levels of decidual CD4+T-cells in the RU486 group that exhibited a higher level of the proinflammatory cytokine interferon-γand a lower level of the anti-inflammatory cytokines,IL-4 and IL-10.Conclusions:We report a new mechanism of RU486-induced abortion via the regulation of innate cell Mφactivation and the adaptive response of CD4+T-cells present in the decidua but not the periphery.展开更多
Objective:To investigate the frequency and function of Tim-3^(+)CD8^(+)T cells in the third trimester of normal pregnancies(NPs)and preeclamptic(PE)pregnancies.Methods:T-cell immunoglobulin mucin-3(Tim-3)expression le...Objective:To investigate the frequency and function of Tim-3^(+)CD8^(+)T cells in the third trimester of normal pregnancies(NPs)and preeclamptic(PE)pregnancies.Methods:T-cell immunoglobulin mucin-3(Tim-3)expression levels of CD8^(+)T cells in the decidua,peripheral blood,and umbilical cord blood obtained from women showing NPs and PE pregnancies were analyzed using flow cytometry.Decidual CD8^(+)T cells were cultured in the presence of recombinant human carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1)protein and/or Tim-3-specific neutralizing antibodies for analyzing CD107a and intracellular cytokine expression.The placental CEACAM1 protein expression was analyzed using immunohistochemistry.Results:Tim-3^(+)CD8^(+)T cells were more abundant in the decidua than in the peripheral blood.Tim-3 expression in the decidual CD8^(+)T cells was significantly lower in PE patients.Decidual Tim-3^(+)CD8^(+)T cells from PE patients expressed higher levels of CD107a and the Th1-type cytokine IFN-γ,but lower levels of the Th2-type cytokine IL-4.CEACAM1 altered the CD107a,IFN-γ,and IL-4 levels;this was reversed by anti-Tim-3 antibodies.The CEACAM1 protein levels were lower in the placental tissues of women with PE pregnancies than in those of women with NPs.Conclusions:Abnormal CEACAM1/Tim-3 regulation may participate in the development of PE,accompanied by disturbed Th2 cell predominance and higher cytotoxicity of decidual CD8^(+)T cells.展开更多
Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immu...Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.展开更多
Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until part...Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.展开更多
Decidual natural killer(dNK)cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnanc...Decidual natural killer(dNK)cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy.However,the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined.Here,we identified a subtype of dNK cells characterized as having a CD3-CD56^brightCD25^+phenotype.We found that CD56^brightCD25^+NK cells preferentially localize to the maternal/fetal interface during early human pregnancy.CD25^+dNK cells account for approximately 75%of CD25-expressing decidual immune cells(DICs).However,less than 5%of CD25-positive peripheral blood mononuclear cells are CD25^+NK cells.Furthermore,CD25^+and CD25^-dNK cells exhibit distinct phenotypes:CD25^+dNK cells display a more activated phenotype and greater cytokine-secreting capacity.Interestingly,coculture of peripheral NK(pNK)cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells,resulting in increased expression of activation markers and cytokine production by pNK cells.In addition,we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25^+dNK cells and contributes to the accumulation of CD3^-CD56^brightCD25^+dNK cells at the maternal/fetal interface.Thus,our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3^-CD56^brightCD25^+dNK cells,which exert a regulating effect at the maternal/fetal interface.展开更多
The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells （DSCs）, decidual immune cells （DICs） and embryo-d...The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells （DSCs）, decidual immune cells （DICs） and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th 1-type and Th2-type cytoki nes by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-IO production in trophoblasts, and IL-IO production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon （IFN）-7 expression in DSCs, and tumor-necrosis factor （TNF）-a expression in DICs. No change was seen in Thl-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Thl-type cytokines IFN-y and TNF-a, and downregulated the production of the Th2-type cytokines IL-4 and IL-IO, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Thl-type cytokine TNF-a and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-IO in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk viathe CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy.展开更多
Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is ...Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia.Galectin-9(Gal-9)has a wide variety of regulatory functions in innate and adaptive immunity during infection,tumor growth,and organ transplantation.Methods:We utilized immortalized human first-trimester EVT cells(HTR8/SVneo)for our functional study.We examined the effects of Gal-9 on viability,proliferation,and invasion of HTR8/SVneo cells,as well as on matrix metalloproteinase-2(MMP-2)production in HTR8/SVneo cells.Furthermore,we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells’invasion.Results:We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion.Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3,not CD44,and subsequently increased MMP-2 production.Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells.Conclusion:Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.展开更多
Mesenchymal stem cells(MSCs)with pluripotency,wide origin and strong migration ability,but low immunogenicity and lack of ethical controversies,have been intensely investigated for clinical applications within the las...Mesenchymal stem cells(MSCs)with pluripotency,wide origin and strong migration ability,but low immunogenicity and lack of ethical controversies,have been intensely investigated for clinical applications within the last decades.Our previously published data in this issue of Cellular and Molecular Immunology demonstrated that adoptive transfer of MSCs can prevent fetal loss in lipopolysaccharide-induced and spontaneous abortion models via a paracrine effect and a cell contact-dependent manner.展开更多
In the published version of Fig.2b and Fig.6d,the same HMOX1 western blot band was inadvertently used in two separate figure panels,although both figures were about HMoX1 expression in three subsets of decidual macrop...In the published version of Fig.2b and Fig.6d,the same HMOX1 western blot band was inadvertently used in two separate figure panels,although both figures were about HMoX1 expression in three subsets of decidual macrophages and peripheral monocytes.展开更多
基金supported by the Shanghai Municipal Science and Technology Major Project(grant No.2017SHZDZX01).
文摘During the coronavirus disease(COVID-19)epidemic,there have been concerns about the impact of vaccines on people’s fertility,including the fertility of those who are currently preparing for pregnancy and those who might become pregnant in future.However,there is still a lack of research on the effect of the COVID-19 vaccine on male fertility,and it is not surprising that couples and donors have concerns regarding vaccination.In this study,a retrospective cohort study was conducted to examine semen quality before and after receipt of the inactivated COVID-19 vaccine.There were no statistically significant changes in semen parameters(volume,sperm concentration,progressive motility,and total progressive motile count)after two doses of vaccine(all P>0.05).In summary,our study updates the most recent studies on the effects of the COVID-19 vaccine on male fertility,and the information from this study could be used to guide fertility recommendations for assisted reproductive technology(ART)patients and donors.
基金Scientific research project of Hebei administration of traditional Chinese medicine (2019238).
文摘Objective:To observe the effects of Ginger moxibustion combined with iontophoresis with traditional Chinese medicine on the improvement of symptoms, serum platelet activating factor (PAF) level and uterine artery pulsation index in patients with primary dysmenorrhea.Methods 114 patients with primary dysmenorrhea who were treated in our hospital from August 2017 to February 2019 were divided into two groups according to the different treatment schemes. 57 patients in the control group were treated with ibuprofen capsules, and 57 patients in the study group were treated with Ginger moxibustion combined with iontophoresis with traditional Chinese medicine. After three menstrual cycles of treatment, the curative effect was evaluated and the improvement of symptoms was counted. PAF, PAF-AH and platelet adhesion rate were compared, uterine artery hemodynamics was measured, and levels of serum hs-CRP and IL-6 were measured.Results The overall response rate of the study group was significantly higher than that of the control group (P < 0.05). After treatment, the scores of different symptoms in the two groups were significantly lower than those before treatment (P < 0.05), and the scores of different symptoms in the study group were significantly lower than those in the control group (P < 0.05). After treatment, PAF and platelet adhesion rate in the two groups were significantly lower than those before treatment (P < 0.05), PAF-AH was significantly higher than that before treatment (P < 0.05), and PAF and platelet adhesion rate in the study group were significantly lower than those in the control group (P < 0.05), PAF-AH was significantly higher than that in the control group (P < 0.05). After treatment, the pulsation index, resistance index and peak systolic-diastolic ratio in the study group were significantly lower than those before treatment (P < 0.05), and the pulsation index, resistance index and peak systolic-diastolic ratio in the study group were significantly lower than those in the control group (P < 0.05). After treatment, the levels of serum hs-CRP and IL-6 in the two groups were significantly lower than those before treatment (P < 0.05), and the levels of serum hs-CRP and IL-6 in the study group were significantly lower than those in the control group (P < 0.05).Conclusions Ginger moxibustion combined with iontophoresis with traditional Chinese medicine is helpful to improve the overall response rate of primary dysmenorrhea treatment, reduce the score levels of different symptoms, rationally improve PAF, PAF-AH, platelet adhesion rate, and the pulse index, resistance index, peak systolic-diastolic ratio are decreased significantly, and serum hs-CRP and IL-6 levels tend to be normal.
基金This study was supported by grants from the National Natural Science Foundation of China(81490741 and 81401224)the Ministry of Science and Technology of the People’s Republic of China(2016YFC1000208 and 2017YFC1001401).
文摘Macrophages are crucial for a successful pregnancy, and malfunctions of decidual macrophages correlate with adverse pregnancyoutcomes, such as spontaneous abortion and preeclampsia. Previously, decidual macrophages were often thought to be a singlepopulation. In the present study, we identified three decidual macrophage subsets, CCR2−CD11cLO (CD11clow, ~80%), CCR2−CD11cHI (CD11chigh, ~5%), and CCR2+CD11cHI (CD11chigh, 10–15%), during the first trimester of human pregnancy by flowcytometry analysis. CCR2−CD11cLO macrophages are widely distributed in the decidua, while CCR2−CD11cHI and CCR2+CD11cHImacrophages are primarily detected close to extravillous trophoblast cells according to immunofluorescence staining. According toRNA sequencing bioinformatics analysis and in vitro functional studies, these three subsets of macrophages have differentphagocytic capacities. CCR2+CD11cHI macrophages have pro-inflammatory characteristics, while the CCR2−CD11cHI population issuggested to be anti-oxidative and anti-inflammatory due to its high expression of critical heme metabolism-related genes,suggesting that these two subsets of macrophages maintain an inflammatory balance at the leading edge of trophoblast invasionto facilitate the clearance of pathogen infection as well as maintain the homeostasis of the maternal-fetal interface. The presentstudy physiologically identifies three decidual macrophage subsets. Further clarification of the functions of these subsets willimprove our understanding of maternal-fetal crosstalk in the maintenance of a healthy pregnancy.
基金funded by Shanghai Science and Technology Committee(17ZR1403300).
文摘Objective:Female reproductive aging is characterized by reduced responsiveness of the hypothalamus to E2-positive feedback,which can result in alterations of gene expression and luteinizing hormone(LH)surge dysfunction.We hypothesize that age-related changes in E2-responsive gene expression are due to altered histone acetylation by histone deacetylases(HDACs)or estrogen receptor-alpha(ERα)coactivators with histone acetyltransferase(HAT)activity.Methods:In the present study,young and middle-aged female rats were ovariectomized(OVX)and treated with E2 or oil once per day for 2 days.At the time of the expected LH surge,the anterior and posterior hypothalami were dissected,and gene expression of 11 HDACs and 4 ERαcoactivators with HAT activity was measured using real-time polymerase chain reaction.Results:In the anterior hypothalamus,age affected the gene expression of 3 HDACs(Hdac3,Hdac5,and Hdac11)and 2 ERαcoactivators(Src2 and Crebbp).E2 treatment significantly decreased mRNA levels of 4 HDACs(Hdac4,Hdac5,Hdac10,and Hdac11)and 2 ERαcoactivators(Src2 and Crebbp)in young females(3-4 months).However,none of the genes responded to E2 in the middle-aged females(9-11 months),except Hdac10.In the posterior hypothalamus,age influenced Hdac5 and Src1 mRNA expression.E2 treatment increased Hdac4 and Crebbp mRNA levels in the young but not middle-aged females.Conclusions:These data suggest that E2 regulates HDACs and ERαcoactivators with HAT activity in an age-and E2-dependent manner,which may contribute to the age-related gene expression changes on the day of LH surge in female reproductive aging.
基金supported by the National Key R&D Program of China(Grant nos.2017YFC1001403 to MRD and 2017YFC1001404 to DJL)the Nature Science Foundation from National Nature Science Foundation of China(Grant Nos.31970859,81630036 to MRD,and 31900663 to YHL)+1 种基金the Program of Shanghai Academic/Technology Research Leader(Grant No.17XD 1400900 to MRD)the Innovation oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation(Grant No.CX20172 to MRD).
文摘Objective:Mifepristone(RU486),one of the most common medications for artificial abortion,attenuates the immunoregulatory effects of progesterone.However,the specific immune regulatory mechanism of RU486 in abortion remains unknown.We intended to investigate the immunomodulatory effects of RU486 on abortion.Methods:Sixty female mice were divided into the control group(0 mg RU486)and RU486 group(2 mg/kg RU486).The uterus,peripheral blood,and spleen were obtained for isolation of specific cell types.The population and phenotype of immune cells in the decidua,peripheral blood,and spleen were analyzed using flow cytometry.Statistical differences between groups were determined using two-tailed t-test.For all statistical tests,P<0.05 was considered statistically significant.Results:RU486 effectively induced abortion in pregnant mice,with a significantly higher number of decidual macrophages(dMφ)(control group=25.55%±2.467%,RU486 group=19.41%±1.423%;P<0.05),especially the major histocompatibility complex II high subset.No difference in Mφnumber was observed in the spleen or peripheral blood.Moreover,the dMφfrom mice with RU486-induced abortion displayed a remarkable activated phenotype,with increased expressions of inducible nitric oxide synthase,tumor necrosis factor-α,and interleukin(IL)-12 but decreased expressions of arginase-1 and IL-10.We also found elevated levels of decidual CD4+T-cells in the RU486 group that exhibited a higher level of the proinflammatory cytokine interferon-γand a lower level of the anti-inflammatory cytokines,IL-4 and IL-10.Conclusions:We report a new mechanism of RU486-induced abortion via the regulation of innate cell Mφactivation and the adaptive response of CD4+T-cells present in the decidua but not the periphery.
基金National Natural Science Foundation of China(31700799,31970859,81601311,and 81630036)Shanghai Sailing Program(17YF1411600)+2 种基金Training Program for Young Talents of the Shanghai Health System(2018YQ07)Shanghai Chenguang Program(18CG09)Development Fund of Shanghai Talents(2018110)。
文摘Objective:To investigate the frequency and function of Tim-3^(+)CD8^(+)T cells in the third trimester of normal pregnancies(NPs)and preeclamptic(PE)pregnancies.Methods:T-cell immunoglobulin mucin-3(Tim-3)expression levels of CD8^(+)T cells in the decidua,peripheral blood,and umbilical cord blood obtained from women showing NPs and PE pregnancies were analyzed using flow cytometry.Decidual CD8^(+)T cells were cultured in the presence of recombinant human carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1)protein and/or Tim-3-specific neutralizing antibodies for analyzing CD107a and intracellular cytokine expression.The placental CEACAM1 protein expression was analyzed using immunohistochemistry.Results:Tim-3^(+)CD8^(+)T cells were more abundant in the decidua than in the peripheral blood.Tim-3 expression in the decidual CD8^(+)T cells was significantly lower in PE patients.Decidual Tim-3^(+)CD8^(+)T cells from PE patients expressed higher levels of CD107a and the Th1-type cytokine IFN-γ,but lower levels of the Th2-type cytokine IL-4.CEACAM1 altered the CD107a,IFN-γ,and IL-4 levels;this was reversed by anti-Tim-3 antibodies.The CEACAM1 protein levels were lower in the placental tissues of women with PE pregnancies than in those of women with NPs.Conclusions:Abnormal CEACAM1/Tim-3 regulation may participate in the development of PE,accompanied by disturbed Th2 cell predominance and higher cytotoxicity of decidual CD8^(+)T cells.
文摘Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.
文摘Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications.
基金This work was supported by the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission(STCSM)(12JC1401600 to DJL)the Key Project of Shanghai Municipal Education Commission(MECSM)(14ZZ013 to MRD)+1 种基金the Nature Science Foundation from National Nature Science Foundation of China(NSFC)(NSFC31270969 to DJLNSFC81070537,NSFC31171437 and NSFC81370770 to MRD,NSFC31300751 to HLP,NSFC81370730 to QF).
文摘Decidual natural killer(dNK)cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy.However,the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined.Here,we identified a subtype of dNK cells characterized as having a CD3-CD56^brightCD25^+phenotype.We found that CD56^brightCD25^+NK cells preferentially localize to the maternal/fetal interface during early human pregnancy.CD25^+dNK cells account for approximately 75%of CD25-expressing decidual immune cells(DICs).However,less than 5%of CD25-positive peripheral blood mononuclear cells are CD25^+NK cells.Furthermore,CD25^+and CD25^-dNK cells exhibit distinct phenotypes:CD25^+dNK cells display a more activated phenotype and greater cytokine-secreting capacity.Interestingly,coculture of peripheral NK(pNK)cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells,resulting in increased expression of activation markers and cytokine production by pNK cells.In addition,we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25^+dNK cells and contributes to the accumulation of CD3^-CD56^brightCD25^+dNK cells at the maternal/fetal interface.Thus,our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3^-CD56^brightCD25^+dNK cells,which exert a regulating effect at the maternal/fetal interface.
文摘The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells （DSCs）, decidual immune cells （DICs） and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th 1-type and Th2-type cytoki nes by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-IO production in trophoblasts, and IL-IO production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon （IFN）-7 expression in DSCs, and tumor-necrosis factor （TNF）-a expression in DICs. No change was seen in Thl-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Thl-type cytokines IFN-y and TNF-a, and downregulated the production of the Th2-type cytokines IL-4 and IL-IO, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Thl-type cytokine TNF-a and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-IO in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk viathe CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy.
基金This work was supported by the National Basic Research Program of China(2015CB9433002017YFC1001400)the National Nature Science Foundation of China(81630036,91542116,31570920,31700799)+2 种基金the Program of Shanghai Academic/Technology Research Leader(17XD1400900)Innovation‑oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation(No.CX2017‑0X)the Shanghai Sailing Program(17YF1411600).
文摘Objective:Adequate extravillous trophoblast(EVT)invasion plays a crucial role in the establishment of successful pregnancy.Insufficient trophoblast migration and invasion can result in defective placentation,which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia.Galectin-9(Gal-9)has a wide variety of regulatory functions in innate and adaptive immunity during infection,tumor growth,and organ transplantation.Methods:We utilized immortalized human first-trimester EVT cells(HTR8/SVneo)for our functional study.We examined the effects of Gal-9 on viability,proliferation,and invasion of HTR8/SVneo cells,as well as on matrix metalloproteinase-2(MMP-2)production in HTR8/SVneo cells.Furthermore,we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells’invasion.Results:We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion.Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3,not CD44,and subsequently increased MMP-2 production.Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells.Conclusion:Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.
文摘Mesenchymal stem cells(MSCs)with pluripotency,wide origin and strong migration ability,but low immunogenicity and lack of ethical controversies,have been intensely investigated for clinical applications within the last decades.Our previously published data in this issue of Cellular and Molecular Immunology demonstrated that adoptive transfer of MSCs can prevent fetal loss in lipopolysaccharide-induced and spontaneous abortion models via a paracrine effect and a cell contact-dependent manner.
文摘In the published version of Fig.2b and Fig.6d,the same HMOX1 western blot band was inadvertently used in two separate figure panels,although both figures were about HMoX1 expression in three subsets of decidual macrophages and peripheral monocytes.
