RESUMEN
Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)α on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXRα expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-α. Interestingly, under physiological flow conditions, TNF-α-induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-α-induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-α and MCP-1 release. Suppression of RXRα expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-κB pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXRα/peroxisome proliferator-activated receptor (PPAR)γ interaction, since endothelial PPARγ silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPARγ interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-α-induced mononuclear leukocyte arrest by 60-65%. In vivo, bexarotene dose-dependently inhibited TNF-α-induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease.
Asunto(s)
Inhibición de Migración Celular/inmunología , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/patología , PPAR gamma/metabolismo , Receptor alfa X Retinoide/agonistas , Bexaroteno , Comunicación Celular/efectos de los fármacos , Comunicación Celular/inmunología , Línea Celular , Inhibición de Migración Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Endotelio Vascular/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Leucocitos Mononucleares/efectos de los fármacos , Microcirculación/efectos de los fármacos , Microcirculación/inmunología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inmunología , PPAR gamma/fisiología , Receptor alfa X Retinoide/biosíntesis , Receptor alfa X Retinoide/fisiología , Tetrahidronaftalenos/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/fisiología , Arterias Umbilicales/efectos de los fármacos , Arterias Umbilicales/inmunología , Arterias Umbilicales/patología , Molécula 1 de Adhesión Celular Vascular/sangreRESUMEN
There is a difference in the susceptibility to inflammation between the umbilical vein (UV) and the umbilical arteries (UAs). This led us to hypothesize that there is an intrinsic difference in the pro-inflammatory response between UA and UV. Real-time quantitative RT-PCR and microarray analysis revealed higher expression of interleukin (IL)-1beta and IL-8 mRNA in the UV and differential expression of 567 genes between the UA and UV associated with distinct biological processes, including the immune response. Differential expression of human leukocyte antigen (HLA)-DRA mRNA between the UA and UV was due to unexpected HLA-DR(+) cells migrating via the umbilical vessels into Wharton's jelly, more frequently in the UV. A significant proportion of these cells co-expressed CD45 and type I pro-collagen, and acquired CD163 or alpha-smooth muscle actin immunoreactivity in Wharton's jelly. Migrating cells were also found in the chorionic and stem villous vessels. Furthermore, the extent of migration increased with progression of gestation, but diminished in intrauterine growth restriction (IUGR). The observations herein strongly suggest that circulating foetal fibrocytes, routing via umbilical and placental vessels, are a reservoir for key cellular subsets in the placenta. This study reports fibrocytes in the human umbilical cord and placenta for the first time, and a novel role for both circulating foetal cells and the umbilical vessels in placental development, which is deranged in IUGR.
Asunto(s)
Desarrollo Embrionario/genética , Feto/citología , Perfilación de la Expresión Génica , Placenta/embriología , Arterias Umbilicales/metabolismo , Venas Umbilicales/metabolismo , Recuento de Células , Femenino , Feto/metabolismo , Fibroblastos/citología , Regulación de la Expresión Génica , Antígenos HLA-DR/inmunología , Humanos , Inmunofenotipificación , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Macrófagos/citología , Análisis por Micromatrices , Modelos Biológicos , Placenta/metabolismo , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Programas Informáticos , Arterias Umbilicales/citología , Arterias Umbilicales/inmunología , Venas Umbilicales/citología , Venas Umbilicales/inmunologíaRESUMEN
PROBLEM: We determined the maternal-fetal transport of immunoglobulin G (IgG) during the third trimester of human pregnancy. METHOD: The concentration of IgG and its subclasses (IgG1-4) was determined in sera of blood samples from 38 pregnancies collected at the time of delivery from a peripheral maternal vein (MV) and from the placental umbilical artery (UA) and vein (UV). Gestational age varied between 28 and 42 weeks (WG). RESULT: Whereas placental weight showed a significant correlation with gestational age, the maternal level of IgG and the ratio of its subclasses did not vary with gestational age. At 28-33 WG (n = 15) the mean values in the UA (5.91 +/- 1.53 g/l) and UV (6.41 +/- 1.57 g/l) for total IgG concentration were lower than in the MV (10.74 +/- 2.55 g/l). At the end of gestation (37-42 WG, n = 12), IgG in both UA (11.21 +/- 1.95 g/l) and UV (12.26 +/- 2.06 g/l) exceeded the maternal concentration (9.69 +/- 1.84 g/l). In addition to the significant positive correlation between IgG concentration in the fetal circulation (UV + UA) and gestational age (28-42 WG), an increase in the positive difference between UV and UA at the end of pregnancy indicates that there is a substantial rise in placental IgG transport capacity. CONCLUSION: All four subclasses IgG1-4 were detectable in the umbilical circulation (28-42 WG). Whereas IgG3 and IgG4 in UA and UV had a similar concentration as in MV and remained unchanged, IgG2 increased with gestation from 0.67/0.74 g/l (UA/UV, 28-33 WG) to 1.29/1.58 g/l (UA/UV, 37-42 WG), but nevertheless remained lower than the level found in the MV (2.65 +/- 1.12 g/l). The main increase in IgG concentration, however, was due to the substantial rise in the transport of IgG1, which increased from 4.37 +/- 1.24 (UA) and 4.94 +/- 1.52 g/l (UV) at 28-33 WG to 8.94 +/- 1.66 (UA) and 10.89 +/- 1.96 g/l (UV) at the end of gestation, which was even higher than the overall IgG concentration in MV.
Asunto(s)
Inmunoglobulina G/metabolismo , Intercambio Materno-Fetal/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Sangre Fetal/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Recién Nacido , Embarazo , Tercer Trimestre del Embarazo , Arterias Umbilicales/inmunología , Venas Umbilicales/inmunologíaRESUMEN
Ten sera from 48 patients with systemic sclerosis were found to be capable of producing cytotoxicity of human umbilical venous and arterial endothelium when co-cultured with peripheral blood mononuclear cells. Fractionation of sera on Ultrogel and the preparation of monomeric IgG by ion exchange and affinity chromatography suggested that the cytotoxicity was mediated by anti-endothelial antibodies capable of pre-sensitizing target cells in a mechanism that resembled antibody-dependent cellular cytotoxicity. These anti-endothelial antibodies together with C1q-binding immune complexes and anti-cardiolipin antibodies were found in 18 of 28 patients so investigated, suggesting that multiple immunological mechanisms may be involved in the pathogenesis of the vascular lesion of systemic sclerosis.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Endotelio Vascular/inmunología , Esclerodermia Sistémica/inmunología , Autoanticuerpos/sangre , Cardiolipinas/inmunología , Células Cultivadas , Complemento C1q/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/etiología , Arterias Umbilicales/inmunología , Venas Umbilicales/inmunología , Factor de von Willebrand/análisisRESUMEN
Total serum IgE levels were determined in 136 newborns and their mothers and in 54 of their fathers, using the paper radioimmunosorbent test (PRIST) technique. IgE specific antibodies for house dust (Dermatophagoides pteronyssinus), orchard grass, timothy grass, and cow's milk were measured with the radioallergosorbent test (RAST). One hundred thirty-three RAST assays were negative in newborns, and in three cases RAST for cow's milk was positive. Cord blood IgE ranged from 0 to 5.5 IU/ml (mean 0.32 +/- 0.54 IU/ml); levels were significantly (p less than 0.05) higher when maternal IgE was over 100 IU/ml and when mothers had received progesterone therapy during the pregnancy. Salbutamol administration or tobacco smoking during pregnancy did not influence newborn IgE. A clinical follow-up study was conducted in 83 infants for 9 mo. Nine infants developed definite atopic disease, and possible allergic diseases were noted in eight other infants. The IgE level at birth appeared to be more predictive for the development of allergy in infancy than the family history.