Estrogen inhibition of EAE involves effects on dendritic cell function

Estrogen has been found to have suppressive effects on the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. We have investigated the effects of 17beta-estradiol (E2) treatment on dendritic cells (DCs) in two different mouse models of EAE. The frequency of CD11b(+)/CD11c(+) DCs was significantly decreased in the brain of mice protected from EAE induction by E2 treatment. In addition, the frequency of CD11c(+)/CD8alpha(+) DCs producing tumor necrosis factor (TNF)alpha and interferon (IFN)gamma in the spleen of E2-treated mice was dramatically decreased compared to that in control mice with EAE, demonstrating an effect of E2 on DC function. In order to examine E2 effects on DCs in more detail, splenic DCs were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 to promote maturation. E2 pretreatment was found to suppress the ability of cultured DCs bearing a mature phenotype to present Ag to myelin basic protein (MBP)-specific T cells. Analysis of cytokine production demonstrated that E2 decreased TNFalpha, IFNgamma and IL-12 production in mature DCs. In addition, MBP-specific T cells cocultured with E2-pretreated mature DCs in the presence of antigen demonstrated a shift towards production of Th2 cytokines IL-4 and IL-10 and a concomitant decrease in the production of Th1 cytokines TNFalpha and IFNgamma. Thus, E2 treatment appears to have multiple effects on the DC population, which may contribute to a down-regulation or block in the activation of Th1 cells involved in the induction of EAE.