Dexamethasone Inhibits Maturation and Alters Function of Monocyte-Derived Dendritic Cells from Cord Blood

Abstract

Critically ill infants are treated with dexamethasone (Dx) and other glucocorticoids to reduce inflammation and to promote lung and cardiac function. The neonatal immune system is immature, so neonatal dendritic cells (DCs) might be especially sensitive to glucocorticoid-mediated immunosuppression. To test this, we compared Dx treatment of monocyte-derived DCs from cord (CB) and adult blood (AB). Dx decreased CD1a levels on both AB and CB DCs. CB-treated cells also exhibited decreased expression of CD83 and increased expression of CD14, alterations not observed in AB DCs. Characteristic immature endocytic activity was sustained and enhanced in Dx-treated CB DCs, whereas AB DCs matured normally. Maintenance of endocytosis corresponded with CD14 expression. Dx markedly increased CB DC IL-10, a T cell helper 2 (Th2)-preferential cytokine, while reducing IL-12, a counterbalancing Th1 cytokine. AB DCs were also affected, but increases in IL-10 and decreases in IL-12 were more modest. Dx treatment also inhibited DC-induced T cell proliferation, but CB DCs were inhibited more. In short, neonatal DCs seemed to be especially sensitive to the immunosuppressive effects of Dx as indicated by altered phenotype, endocytic function, ability to stimulate T cells, and cytokine shift favoring Th2. These alterations in DC function are consistent with an increased risk for certain infections and atopic diseases. Cytokines that are produced by the placenta dampen allograft rejection and are thought to enhance the intrauterine survival of the fetus (1). This immune attenuation tends to direct an immune response toward T helper (Th) 2 and to weaken development of Th1-mediated immunity in newborns (2). The full range of adaptive immunity is gradually acquired through exposure to antigens that induce Th1 T cell responses and the development of a balanced immune system. When mothers go into premature labor, glucocorticoids, such as dexamethasone (Dx), are widely prescribed to enhance fetal lung maturation (3). In addition, glucocorticoids are used postnatally to reduce lung inflammation and to improve cardiovascular status in critically ill infants (4). Dx-treated infants have alterations in immune responsiveness as indicated by significantly reduced antibody responses after immunization (5); increased infections (6); multiple short-term adverse complications such as intestinal perforation (7-9), hypertension, and hypertrophic cardiomyopathy (10,11); and long-term effect such as increased risk for airway hyperresponsiveness and decreased pulmonary function (12,13).Several in vitro studies that were designed to identify the stage of maturation of each immune cell lineage in normal newborns have revealed that neonate naïve T (14 -16) and B (17,18)

The Impact of Hyperoxia on the Neonatal and Adult Developing Dendritic Cell

“…Individually or in combination, these findings could explain why the adult or more mature cells appeared more susceptible to the damaging effects of hyperoxia in this study. The relative predominance of anti-inflammatory cytokines such as IL-10 in the newborn compared with adult (10,31,32) may also contribute to a protective mechanism toward neonate cells against hyperoxia. We acknowledge that further work needs to clarify any effect of DMSO, the diluent used in stabilizing the dye in quantifying the oxygen reactive species, on the membrane permeability (33) of CB-versus AB-DC.…”

“…Adult blood was collected by venipuncture from healthy volunteers. The dendritic progenitor cells were extracted from mononuclear cells as described previously (10). Briefly, the mononuclear cells were separated from red cells by sedimentation with a solution of hydroxyethyl starch followed by density centrifugation over Histopaque-1077 (Sigma Chemical Co., St. Louis, MO).…”

Role of Dendritic Cells in the Regulation of Maternal Immune Responses to the Fetus During Mammalian Gestation

“…Over the last decade, it has become clear that maturation and function of DC may be influenced by gluocorticoids (deJong, 1999;Mainali, 2005;Piemonti, 1999;Rozkova, 2006). In especial, glucocorticoids are assumed to induce regulatory immature DC (Pedersen, 2004;Xia, 2005).…”

Perinatal Immunotoxicity: Why Adult Exposure Assessment Fails to Predict Risk

“…Dexamethasone exposure of these immature cells prevents their maturation to promote T H 1 responses and locks in the T H 2 IgE-promoting phenotype. The T H 2 skewing effect appears to be long-lasting (Mainali et al 2005). This type of early-life-stage–restricted immunotoxicity appears to contribute to an increased risk of atopy and asthma.…”