Minyue Dong

Placental imbalance of Th1- and Th2-type cytokines in preeclampsia

Objectives.  To characterize the changes in the level of T helper 1 (Th1)‐ [interleukin (IL)‐2 and tumor necrosis factor (TNF)‐α] and Th2‐type cytokine (IL‐10) and the ratios of Th1/Th2 (IL‐2/IL‐10 and TNF‐α/IL‐10) in placentae from women with preeclampsia and women with gestational hypertension.

Serum adiponectin, leptin and soluble leptin receptor in pre-eclampsia.

Objectives: To delineate the changes in serum levels of adiponectin, leptin and soluble leptin receptor, and in the free leptin index in women with pre‐eclampsia.

The Effect of Trophoblasts on T Lymphocytes: Possible Regulatory Effector Molecules - A Proteomic Analysis

Background/Aims: Tolerance of T lymphocytes at the feto-maternal interface is necessary to sustain normal pregnancy. The present investigation aimed to observe the regulatory effects on T lymphocytes by human trophoblasts and to explore possible effector molecules. Methods: Conditioned media was made by trophoblast culture or villous explant culture for T lymphocyte proliferation and proteomic analysis. Lymphocyte proliferation was tested by thymidine incorporation. Messenger RNA for indoleamine 2,3- dioxygenase (IDO) was detected by RT-PCR and tryptophan was assayed. The protein profile of conditioned media was assessed with shotgun mass-spectrometry and the identified proteins were bioinformatically analyzed. Human chorionic gonadotropin (HCG), human chorionic somatomammotropin (HCS), interleukin (IL)-2, 4, 10 and tumor necrosis factor (TNF)- α were assayed with radioimmunoassay (RIA). Results: T Lymphocyte proliferation was inhibited by conditioned medium in a dose-dependant manner. Inhibition of IDO during previous conditioning or addition of tryptophan to the conditioned medium partly restored T lymphocyte proliferation. mRNA for IDO was expressed in trophoblasts and chorionic villi. The concentrations of tryptophan were 19.01 and 3.79 µmol/L in unconditioned and conditioned media respectively. By proteomic procedures, 548 proteins were found in placenta-conditioned medium. Among these proteins were some proteins inhibiting T lymphocytes including HCG, HCS, AFP, pregnancy-specific beta 1-glycoprotein (SP1), glycodelin, transforming growth factor β2, thrombospondin-1, pigment epithelium-derived factor (PEDF), galectin-1, and macrophage migration inhibitory factor. HCG and HCS were also detected with RIA, however, no interleukins were detected in conditioned media with RIA or proteomic analysis. Conclusions: Trophoblasts inhibit T lymphocyte through IDO-mediated tryptophan depletion and placenta-derived immunoregulatory factors. Immunological tolerance at maternal-fetal interface represents a synergistic effect of these substances and a complex mechanism involving endocrine and immune networks.

Serum resistin in gestational diabetes mellitus and early postpartum

Objectives  To observe the alterations in serum resistin in gestational diabetes (GDM) and the early postpartum period, and compare this to nondiabetic pregnancies in order to evaluate the role of serum resistin in gestational diabetes mellitus.

Serum visfatin levels in late pregnancy and pre-eclampsia.

Objectives. To characterise the changes in serum visfatin levels in late normal pregnancy and pre‐eclampsia. Methods. Twenty‐seven women with pre‐eclampsia were recruited. Twenty‐eight women in the third trimester of normal pregnancy served as pregnant control and 28 healthy non‐pregnant women as non‐pregnant control. Serum levels of visfatin were measured with an enzyme‐linked immunosorbent assay. Results. The means of serum visfatin were 626.4±45.5ng/ml (mean±SEM) in non‐pregnant control, 695.9±92.5ng/ml in pregnant control, and 308.3±80.0 ng/ml in pre‐eclampsia, respectively, and were significantly different among the groups (p <0.001). Visfatin level was significantly lower in pre‐eclampsia compared to non‐pregnant control (p = 0.004) and pregnant control (p <0.001). Women with severe pre‐eclampsia had a significantly lower serum visfatin level than those with mild pre‐eclampsia (114.6±80.9 versus 425.2±122.1ng/ml, p = 0.037). Conclusions. A decrease in visfatin level was demonstrated in pre‐eclampsia, suggesting that visfatin and adipokine‐associated metabolic abnormalities are involved in the pathogenesis of the disease.

Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss

Early pregnancy loss (EPL) is one of the most common complications of human reproduction. Combined with our previous proteomic studies on villous and decidual tissues of EPL, we found that alterations of the proteins involved in oxidative stress (OS), unfolded protein response (UPR) and proteolysis presented a complex and dynamic interaction at the maternal-fetal interface. In the present study, we developed a cell model of OS using normal decidual cells to examine cell viability and expression levels of proteins related to endoplasmic reticulum stress (ER stress) and UPR. We found that glucose regulated protein 78 (GRP 78) and ubiquitinated proteins were significantly up-regulated in hydrogen peroxide (H2O2) treated decidual cells in a dose-dependent manner. Excessive OS could influence proper function of UPR by decreasing VCP in decidual cells, thereby leading to cell damage as well as inhibition of cell growth and activation of apoptosis. Furthermore, when pretreated with MG 132, a pharmacological inhibition of the proteasome, the H2O2 treated decidual cells became less viable and could not up-regulate the expression level of GRP 78 to resolve the protein-folding defects, which indicating that malfunction of UPR in decidual cells might aggravate the inhibitory effect of OS in decidual cells. The present results reveal that abnormal protein profiles associated with OS induced ER stress and malfunction of UPR might be involved in the development of EPL, and OS and ER stress are potential targets for pregnant care and prognosis in normal pregnancy and its disorders.

Placental trophoblasts shifted Th1/Th2 balance toward Th2 and inhibited Th17 immunity at fetomaternal interface.

Liu F, Guo J, Tian T, Wang H, Dong F, Huang H, Dong M. Placental trophoblasts shifted Th1/Th2 balance toward Th2 and inhibited Th17 immunity at fetomaternal interface. APMIS 2011.

Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia.

BACKGROUND Preeclampsia, a pregnancy-specific complication occurring in the second half of human pregnancy and one of the leading causes for perinatal mortality and morbidity, is characterized by the onset of hypertension and proteinuria. We measured circulating adipocyte fatty acid binding protein (AFABP) and retinol binding protein-4 (RBP-4) in patients with preeclampsia. METHODS Twenty-seven healthy non-pregnant women, 27 healthy pregnant women at third trimester and 26 women with preeclampsia were recruited and blood samples were taken. Concentrations of serum AFABP and RBP-4 were measured with ELISA. RESULTS There were significant differences in serum AFABP (median: 0.99, 0.93 and 1.81ng/ml, respectively, P<0.001) and RBP-4 (mean: 3.16, 2.65 and 4.27ng/ml, respectively, P=0.022) among non-pregnancy, normal pregnancy and preeclampsia. Serum AFABP was significantly higher in preeclampsia than non-pregnancy (P<0.001) and normal pregnancy (P=0.001). Serum RBP-4 was significantly higher in preeclampsia than normal pregnancy (P=0.007) but not non-pregnancy (P=0.061). There were no significant differences in serum RBP-4 and AFABP between non-pregnancy and normal pregnancy. Serum RBP-4 was significantly higher in severe than mild preeclampsia (mean: 5.15 vs 2.84ng/ml, P=0.046). There was no significant difference in serum AFABP between mild and severe preeclampsia. CONCLUSION Increased circulating AFABP and RBP-4 concentrations were demonstrated, suggesting it be an important pathophysiology of preeclampsia.

Alteration of peripheral CD4+CD25+ regulatory T lymphocytes in pregnancy and pre-eclampsia

Objectives. To clarify the change of peripheral CD4+CD25+ regulatory T lymphocytes in normal pregnancy and pre‐eclampsia and to explore its role in the pathogenesis of pre‐eclampsia. Methods. Twenty‐seven women with pre‐eclampsia, 27 with normal third trimester pregnancy and 27 healthy non‐pregnant women were recruited. Blood samples were taken and surface antigen CD4 and CD25 were labelled with fluorescence‐conjugated antibodies. CD4+CD25+ regulatory T cells were analysed by flow cytometry, and the proportion in T cells and the amount of regulatory T lymphocytes were calculated. Results. The amount and the proportion of regulatory T cells were not significantly different among non‐pregnant, normal pregnancy and pre‐eclampsia groups (p>0.05 for both). There were no significant differences in the proportion and the amount of CD4+CD25+ regulatory T cells between mild and severe pre‐eclampsia subgroups (p>0.05 for both). Conclusions. No significant change of peripheral regulatory T cells was observed in the current investigation, suggesting other mechanisms rather than CD4+CD25+ regulatory T cells were involved in the pathogenesis of pre‐eclampsia.

Elevated serum levels of interleukin-15 and interleukin-16 in preeclampsia

A generalized inflammatory response has been considered to be the main pathology and has an important role in the pathogenesis of preeclampsia. The immune aberrations per se and immunomodulatory milieu present in serum need to be elucidated. The purpose of the current investigation was to characterize changes in serum levels of interleukin (IL)-15 and IL-16 in preeclampsia. Thirty-seven women with preeclampsia were recruited and 36 age- and gestational age-matched women with normal pregnancy served as control. Levels of IL-15 and IL-16 were detected with immune assays in all serum samples. We found that serum levels of IL-15 and IL-16 were significantly higher in preeclampsia than in normal pregnancy (p<0.001 for both). There were significant differences in serum IL-15 and IL-16 between mild and severe preeclampsia (p<0.01 for both). Our data corroborate the hypothesis of an increased inflammatory response in preeclampsia, as illustrated by the elevated serum levels of IL-15 and IL-16, suggesting their possible role in the pathogenesis of preeclampsia. These associations may offer insight into the pathophysiology of preeclampsia.