QUANTITATIVE MODELING OF SUPPRESSION OF IgG1, IgG2a, IL-2, and IL-4 RESPONSES TO ANTIGEN IN MICE TREATED WITH EXOGENOUS CORTICOSTERONE OR RESTRAINT STRESS

Abstract

Exposure to toxic chemicals often induces a neuroendocrine stress response leading to increased concentrations of a variety of potentially immunomodulatory mediators. Corticosterone is a major stress-induced mediator that can be immunosuppressive. However, the quantity of corticosterone exposure required to produce particular decrements in particular immunological parameters is not known. Mice treated with various dosages of exogenous corticosterone were compared to mice exposed to a psychogenic stressor (restraint). Cumulative corticosterone exposure in these mice, expressed as the area under the curve (AUC) of corticosterone concentration versus time, was used to develop quantitative models of the effects of corticosterone on the immunoglobulin (Ig) G1 and IgG2a responses to keyhole limpet hemocyanin (KLH) and sheep erythrocytes (sRBC). The production of interleukin (IL)-2 and IL-4 by splenocytes stimulated with KLH in culture was also evaluated. Linear regression models were derived that describe the relationship between the IgG1 and IgG2a responses to KLH. Restraint had a greater effect (at equivalent corticosterone AUC values) than exogenous corticosterone, suggesting that mediators in addition to corticosterone are important in suppression of the IgG1 and IgG2a response to KLH. The production of IL-2 and IL-4 by cultured splenocytes was mostly, but not always, consistent with the changes in IgG1 or IgG2a. For example, the regression lines for IgG2a (a Th1-driven response) and IL-2 (a Th1 cytokine) were not significantly different. The relationships between corticosterone AUC and the IgG1 and IgG2a responses to sRBC were nonlinear and characterized by enhanced responses at low to moderate AUC values. The quantitative models developed here have implications for risk assessment in immunotoxicology.