Prenatal Stress Diminishes the Cytokine Response of Leukocytes to Endotoxin Stimulation in Juvenile Rhesus Monkeys

Abstract

This study investigated whether exposing the fetal primate to repeated episodes of maternal stress would have long-lasting effects on the endotoxin-induced cytokine response and corticosteroid sensitivity of peripheral blood cells in juvenile animals. Pregnant rhesus monkeys were acutely aroused on a daily basis for 6 wk using an acoustical startle protocol, either early or late in the 24-wk pregnancy. To quantify cytokine responses and corticosteroid sensitivity in their offspring at 2 yr of age, whole blood cultures were stimulated with lipopolysaccharide and incubated with dexamethasone (DEX). TNFα and IL-6 levels were determined in the culture supernatants. The blood samples were collected from undisturbed monkeys under baseline conditions, as well as in an aroused state induced by a 2 h social separation. Juvenile monkeys from stressed pregnancies had significantly lower cellular cytokine responses compared with the undisturbed controls. When DEX was added to the cell cultures, it systematically inhibited TNFα and IL-6 production, bringing the values for control animals down into the range of the prenatally stressed animals. Lipopolysaccharide-induced cytokine production was also markedly suppressed by the experience of acute stress, reducing cytokine responses of controls to the levels found for prenatally disturbed monkeys under baseline conditions. Therefore, this study has demonstrated that prenatal disturbance can induce a lasting change in cytokine biology, which persists well beyond the fetal and infant stage. Further, these effects may be due to elevated hypothalamic-pituitary-adrenal activity in the prenatally stressed animals, because both DEX and acute arousal made the cells from control monkeys appear more similar to those from disturbed pregnancies.