RESUMEN
PROBLEM: Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. METHOD OF STUDY: About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. RESULTS: Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. CONCLUSIONS: Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.
Asunto(s)
Inflamación/sangre , Neovascularización Fisiológica , Placenta/irrigación sanguínea , Adulto , Antitrombinas/sangre , Biomarcadores/sangre , Coagulación Sanguínea/inmunología , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Quimiocina CXCL10/sangre , Quimiocina CXCL11/sangre , Complemento C3a/análisis , Femenino , Humanos , Inflamación/inmunología , Interleucina-4/sangre , Placenta/inmunología , Placenta/metabolismo , Factor de Crecimiento Placentario , Preeclampsia , Embarazo , Proteínas Gestacionales/sangre , Componente Amiloide P Sérico/análisis , Estadísticas no Paramétricas , Factores de Tiempo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (M), one of the major leukocyte populations at the fetal-maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual M with an in vitro M differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) M markers expressed on human decidual M (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual M polarization. M-CSF/IL-10-stimulated and decidual M also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ-stimulated M produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 M-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual M, confirming that M-CSF/IL-10-induced M are closely related to decidual M. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual M with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.
Asunto(s)
Decidua/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Placenta/inmunología , Embarazo/inmunología , Adolescente , Adulto , Diferenciación Celular/inmunología , Separación Celular , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Interleucina-10/inmunología , Factor Estimulante de Colonias de Macrófagos/inmunología , Macrófagos/citología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
CD4(+)CD25(high) regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17beta-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4(dim)CD25(high) Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4(+) population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17beta-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4(dim)CD25(high)Foxp3(+) cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4(+)CD25(-) responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-alpha, and IFN-gamma secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.