Vitamin D decreases expression of NLRP1 and NLRP3 inflammasomes in placental explants from women with preeclampsia cultured with hydrogen peroxide.

This study aimed to evaluate the immunomodulatory effect of vitamin D (VD) on the NLRP1 and NLRP3 inflammasomes in placental explants from preeclamptic (PE) and normotensive (NT) pregnant women. Placental explants from eight PE and eight NT pregnant women were cultured with or without hydrogen peroxide (H2O2), VD or H2O2 + VD. Gene and protein expression of NLRP1, NLRP3, HMGB1, caspase-1, IL-1ß, TNF-α and IL-18 were determined by qPCR and Western blotting/ELISA. Compared to NT pregnant women, the endogenous gene expression of NLRP1, NLRP3, HMGB1, IL-1ß, TNF-α and IL-18 was significantly higher in explants from PE and became decreased after VD treatment. Similarly, VD decreased the protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1ß, TNF-α and IL-18 in PE. Placental explants from NT cultured with H2O2 showed increased gene and protein expression of NLRP1, NLRP3, caspase-1, IL-1ß, TNF-α and HMGB1, while H2O2 was also able to increase TNF-α and caspase-1 gene expression in PE. Treatment with H2O2 + VD decreased gene/protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1ß, TNF-α and IL-18 in PE and NT explants with H2O2. NLRP1 and NLRP3 are upregulated in the PE. VD may play an immunomodulatory role in the placental inflammation and downregulates oxidative stress induced in vitro by H2O2.

Association between cytokine profile and transcription factors produced by T-cell subsets in early- and late-onset pre-eclampsia.

Pre-eclampsia (PE) is an obstetric pathology characterized by abnormal activation of the innate and adaptive immune systems dependent on the imbalance of T helper subsets. The present study aimed to evaluate the gene and protein expression of T helper type 1 (Th1)/Th2/Th17/regulatory T (Treg) cell transcription factors in peripheral blood lymphocytes from pregnant women with PE employing quantitative RT-PCR and flow cytometry techniques, as well as the cytokine profile produced by these CD4+ T-cell subsets in the plasma of pregnant women with PE, classified as early-onset PE (n = 20), late-onset PE (n = 20) and normotensive pregnant women (n = 20). Results showed a higher percentage of CD4+ T cells expressing the RORc transcription factor (Th17) and a lower percentage of cells expressing FoxP3 (Treg) in women with early-onset PE compared with late-onset PE and normotensive groups. A lower gene expression of GATA-3 transcription factor was detected in cells of women with early-onset PE compared with the late-onset PE group. Endogenous plasma levels of interleukin-6 (IL-6), IL-17 and tumour necrosis factor-α were significantly higher in the early-onset PE group than in the late-onset PE and normotensive groups, whereas IL-4 (Th2 profile) and IL-22 (Th17 profile), were not significantly different between the studied groups. The endogenous levels of transforming growth factor-ß and IL-10 were significantly lower in the pre-eclamptic than in the normotensive groups of the same gestational age, with a significant difference between early- and late-onset PE. The results show that in women with PE there is an imbalance between inflammatory and anti-inflammatory profiles in CD4+ T-cell subsets, with polarization to Th17 profiles in the early-onset PE, considered as the severe form of PE.

Association between Placental Lesions, Cytokines and Angiogenic Factors in Pregnant Women with Preeclampsia.

Preeclampsia (PE) is considered the leading cause of maternal and perinatal morbidity and mortality. The placenta seems to play an essential role in this disease, probably due to factors involved in its formation and development. The present study aimed to investigate the association between placental lesions, cytokines and angiogenic factors in pregnant women with preeclampsia (PE). We evaluated 20 normotensive pregnant women, 40 with early-onset PE and 80 with late-onset PE. Placental samples were analyzed for histopathology, immunohistochemistry and determination of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), transforming growth factor-beta 1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), fms-like tyrosine-kinase-1 (Flt-1) and endoglin (Eng) levels. Higher percentages of increased syncytial knots and increased perivillous fibrin deposits, and greater levels of TNF-α, TGF-ß1and Flt-1 were detected in placentas from early-onset PE. Levels of IL-10, VEGF and PlGF were decreased in PE versus normotensive placentas. Both the TNF-α/IL-10 and sFlt-1/PlGF ratios were higher in placental homogenate of early-onset PE than late-onset PE and control groups. The more severe lesions and the imbalance between TNF-α/IL-10 and PlGF/sFlt-1 in placentas from early-onset PE allows differentiation of early and late-onset PE and suggests higher placental impairment in early-onset PE.

High levels of heat shock protein 70 are associated with pro-inflammatory cytokines and may differentiate early- from late-onset preeclampsia.

Preeclampsia (PE), a specific syndrome of pregnancy, can be classified into early and late onset, depending on whether clinical manifestations occur before or after 34 weeks' gestation. We determined whether plasma concentrations of Hsp60 and Hsp70 were related to circulating cytokine levels, as well as kidney and liver functions, in early- and late-onset PE. Two hundred and thirty-seven preeclamptic women (95 with early- and 142 with late-onset PE) were evaluated. Plasma levels of Hsp60, Hsp70, and their specific antibodies, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-10, IL-12, and soluble TNF-α-receptor I (sTNFRI) concentrations, were determined by enzyme-linked immunosorbent assay (ELISA). Concentrations of Hsp70, TNF-α, IL-1ß, IL-12, and sTNFRI were significantly elevated in patients with early-onset PE compared with women with late-onset PE; IL-10 levels were significantly lower in the early-onset PE group. Concentrations of urea, uric acid, proteinuria, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were also significantly higher in early-onset PE. The percentage of infants with intrauterine growth restriction was also significantly higher in women with early-onset PE. There were positive correlations between Hsp70 levels and TNF-α, TNFRI, IL-1ß, IL-12, GOT, GPT, LDH, and uric acid concentrations in early-onset PE group. Thus, early-onset PE was associated with greater maternal and fetal impairment. There are differences in pathophysiology between early- and late-onset PE, highlighting by the difference in Hsp70 levels.