MDSCs in pregnancy and pregnancy-related complications: an update†.

Maternal-fetal immune tolerance is a process that involves complex interactions of the immune system, and myeloid-derived suppressor cells have emerged as one of the novel immunomodulator in the maintenance of maternal-fetal immune tolerance. Myeloid-derived suppressor cells are myeloid progenitor cells with immunosuppressive activities on both innate and adaptive cells through various mechanisms. Emerging evidence demonstrates the accumulation of myeloid-derived suppressor cells during healthy pregnancy to establish maternal-fetal immune tolerance, placentation, and fetal-growth process. By contrast, the absence or decreased myeloid-derived suppressor cells in pregnancy complications like preeclampsia, preterm birth, stillbirth, and recurrent spontaneous abortion have been reported. Here, we have summarized the origin, mechanisms, and functions of myeloid-derived suppressor cells during pregnancy along with the recent advancements in this dynamic field. We also shed light on the immunomodulatory activity of myeloid-derived suppressor cells, which can be a foundation for potential therapeutic manipulation in immunological pregnancy complications.

The abnormal expression of Tim-3 is involved in the regulation of myeloid-derived suppressor cells and its correlation with preeclampsia.

INTRODUCTION: Maternal immune system tolerance to the semi-allogeneic fetus is critical to a successful pregnancy. We previously reported that myeloid-derived suppressor cells (MDSC) was associated with maternal immune imbalance. T cell immunoglobulin and mucin-containing protein 3 (Tim-3)/Galectin-9 (Gal-9) pathway modulates function of various immune cells in maternal-fetal interface. However, the regulatory effects of Tim-3/Gal-9 signaling on MDSCs and its role in preeclampsia (PE) remain unclear. METHODS: In the current study we investigated the expression of Tim-3 on MDSC in preeclampsia (PE) patients to further explore the pathogenesis of PE. RESULTS: The proportion of Tim-3+ M-MDSC (monocytic MDSC) cells was higher in PE patients than in healthy control. Meanwhile, the protein expression of Gal-9, as the ligand of Tim-3, was increased in placenta of PE patients. M-MDSC also expressed a higher level of interferon-γ (IFN-γ) and a lower level of transforming growth factor-ß (TGF-ß) in PE. Furthermore, our study suggested that blocking Tim-3 could attenuate the inhibitory function of MDSC. DISCUSSION: The abnormal expression of Tim-3 on MDSC might be involved in the pathogenesis of PE, and could be a marker to evaluate the immune function in PE.

Preeclampsia exposed offspring have greater body mass index than non-exposed offspring during peripubertal life: A meta-analysis.

BACKGROUND: This study evaluates the effect of preeclampsia on body mass index (BMI) of offspring who were exposed to preeclampsia in utero. METHODS: Data were obtained from studies identified by a literature search in electronic databases. Random-effects metanalyses were conducted to achieve mean difference in BMI, waist circumference, gestation length, and birthweight between preeclampsia exposed (PE) and non-exposed (non-PE) offspring older than 5 years. Metaregression analyses were performed to identify factors affecting offspring BMI. RESULTS: Sixteen studies (11639 PE offspring; age 15.5 years [14.2, 16.8]; 33.3% [32.6, 33.9] males vs 526,576 non-PE offspring; age 15.7 years [15.0, 16.4]; 42.6% [40.6, 44.5] male) were used. Gestation duration and birthweight of PE fetuses were significantly lesser than those of non-PE fetuses (mean difference (MD) -0.66 weeks [-1.25, -0.07]; p = 0.03 and MD -207.9 [-344.0, -71.8]; p = 0.003) respectively. BMI of PE offspring was significantly higher than non-PE offspring (MD 0.54 kg/m2 [0.27, 0.82]; p = 0.0001). Odds of being obese was significantly higher in PE than non-PE offspring (odds ratio 2.12 [1.70, 2.66]; P < 0.00001). Waist circumference was also significantly higher in PE than in non-PE offspring (MD 1.37 cm [0.67, 2.06]; p = 0.0001). Offspring BMI was significantly inversely associated with maternal age in both PE and non-PE groups. CONCLUSION: Preeclampsia poses risk of higher BMI and waist circumference especially to the offspring of older mothers.

Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways.

Metformin (Met) has been found to modify the methylation of H19 and to alter its expression. In addition, IL-27, one of the downstream factors in the H19 signaling pathway, plays an important role in the pathogenesis of pre-eclampsia (PE). In this study, we investigated the molecular mechanism underlying the therapeutic effect of Met in the management of PE both in vivo and in vitro. The role of H19 signaling pathway in PE was validated using online bioinformatics tools, luciferase assays, real-time PCR and Western Blot. A tail-cuff method was used to examine the blood pressures in PE rats with or without Met treatment. Cells exhibited a dose-dependent increase of H19 methylation, which inhibited the expression of H19. Additionally, upon the Met treatment, levels of miR-148-5p and miR-216-3p were both elevated in a dose-dependent manner while levels of p28 mRNA and EBI3 mRNA were both inhibited by Met treatment. Also, H19 was found to regulate the expression of miR-148a-5p and miR-216-3p, while P28 and EBI3 were respectively identified as target genes of miR-148a-5p and miR-216-3p. Therefore, the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways were implicated in the pathogenesis of PE. Met was implicated in the pathogenesis of PE via modulating the H19 signaling pathway. The methylation of H19 reduced H19 expression, which in turn could up-regulate the expression of miR-148-5p/miR-216-3p. And the expressions of subunits of IL-27, P28 and EBI3, were thus suppressed. Therefore, Met-induced inhibition of H19 also led to the reduction of IL-27 expression, TNF-α and IL-6 in vivo.

A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification.

PURPOSE: MLN4924 is a second-generation inhibitor that targets ubiquitin-proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo. METHODS: The impact of MLN4924 on renal cancer cells was determined by measuring viability (MTS), proliferation cell count test and clonogenic assays, cell cycle progression (flow cytometry with propidium iodide staining), apoptosis (flow cytometry with annexin V-FITC labeling) and DNA damage (immunofluorescent staining). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration was analyzed by wound healing assays. A well-established SCID xenograft mouse model was used to evaluate the effects of MLN4924 on tumor growth in vivo. RESULTS: The data showed that MLN4924 induced a dose-dependent cytotoxicity, anti-proliferation, anti-migration, and apoptosis in human renal cancer cells; and caused cell cycle arrested at the G2 phase. In addition, the E2 conjugating enzymes of Neddylation UBE2M played a major role in the proliferation control of renal cancer cells. Finally, we confirmed MLN4924 inhibited tumor growth in a RCC xenograft mouse model with minimal general toxicity. CONCLUSION: We concluded that MLN4924 induces apoptosis and cell cycle arrest. These findings implied that MLN4924 provides a novel strategy for the treatment of RCC.