2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) directly enhances the maturation and apoptosis of dendritic cells in vitro

Abstract

2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) suppresses adaptive immune responses and modulates the function of numerous cells involved in these responses. Our laboratory has shown that dendritic cells (DCs), which are important for the initiation of T-cell-dependent immunity, from TCDD-exposed mice exhibited reduced cell numbers and had altered expression of costimulatory molecules that are critical for the activation of T-cells. To further characterize the effects of TCDD on DCs and to elucidate a potential mechanism of toxicity, we investigated the direct effects of TCDD on DC maturation and survival in vitro. DCs, derived from bone marrow cells, were exposed to TCDD and then treated with TNFα to induced maturation. Apoptosis of bone marrow derived DCs (bmDCs) was induced by activating CD95 on the surface of the cells and was measured by annexin V staining. The TCDD-mediated changes in the expression of genes associated with apoptosis were examined using a pathway-specific c-DNA microarray. The results demonstrate that TCDD-treatment of bmDCs enhanced TNFα-induced maturation, measured as an increase in the expression of major histocompatibility complex class II, CD86, CD40, and CD54. In addition, TCDD exposure significantly augmented CD95-mediated death of bmDCs and altered the transcription of several genes involved in apoptosis. These findings confirm and extend the in vivo effects of TCDD on DC activation, and suggest that TCDD induces these changes, at least in part, via direct effects on the DC. © 2004 Informa UK Ltd All rights reserved.