Dioxins damage dendritic cells

Abstract

The effect of environmental pollutants on the immune system has been a well-studied and controversial topic, with dioxins heading the list of molecules under investigation. Mainly produced as a by-product of the manufacture of materials requiring the use of chlorinated phenol, or as a result of the incineration of chlorinated chemical products, dioxins have been shown to have a multitude of effects on the immune system. Epidemiological analyses of human populations have shown a positive correlation between the level of exposure to environmental dioxins and the susceptibility to infectious diseases. Toxicologists consider the effects on immune function to be among the earliest and most-sensitive indicators of dioxin toxicity.In terms of mechanism, many studies have focused on the effects on thymocyte development, where dioxins, such as TCDD (tetrachlorodibenzo-p-dioxin), induce very specific responses. In dioxin-treated animals, the thymus becomes hypoplasic and there is a preferential emigration of very immature CD4−CD8+ thymocytes. These effects are mediated by a dioxin receptor called the Ah receptor (aryl hydrocarbon receptor). Whether an endogenous ligand for this receptor also exists is not known yet; evidence that bilirubin, a metabolic product of heme with known immunosuppressive effects, might be such a ligand has been presented. The Ah receptor is a transcription factor, the target genes of which include those encoding enzymes that metabolize toxins, such as TCDD. Recent data also indicates that the Ah receptor can antagonize the effects of another transcription factor, NF-κB, an important regulator of immune and inflammatory gene expression. The Ah receptor is highly expressed in thymic epithelium and in thymocytes, and no immunosuppressive effects occur in Ah receptor-deficient mice in response to TCDD.A recent study [1x2,3,7,8-tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Vorderstrasse, B.A. and Kerkliet, N.I. Toxicol. Appl. Pharmacol. 2001; 171: 117–125Crossref | PubMed | Scopus (57)See all References][1] carried out at the Dept of Environmental and Molecular Toxicology at Oregon State University, OR, USA demonstrates that the treatment of mice with TCDD also leads to the premature deletion of dendritic cells in vivo. Interestingly, this deletion might be activation-dependent as the low levels of dendritic cells that were isolated from these mice showed increased expression of ICAM-1, B7-2, CD40 and IL-12. All of these effects were dependent on the Ah receptor. Dendritic cells might therefore be an important target for environmental pollutants, such as dioxins.