Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzio-p-dioxin (TCDD) leads to immune suppression associated with the induction of regulatory T cells (T reg ) expressing the transcription factor Foxp3. The immunological mechanisms of suppression are not well understood however dendritic cells (DC) are considered a key target for AhR-mediated immune suppression. Here we show that activation of AhR by TCDD induces DC indoleamine-2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase-like protein (IDO2). Induction of IDO1 and IDO2 was also found in lung and spleen associated with an increase of the T reg marker Foxp3 in spleen of TCDD-treated C57BL/6 mice, which is suppressed by inhibition of IDO. These data indicate that AhR-activation is an important signaling pathway for IDO expression and suggest a critical role of IDO in the mechanism leading to the generation of T reg that mediates the immune suppression through activation of AhR.
Recent studies have shown that cultures of white rot fungi not favoring the production of lignin and manganese peroxidases are effective in degrading certain xenobiotics. In this study we have used endosulfan as a model xenobiotic to assess the enzymatic mechanisms of pesticide metabolism under ligninolytic (nutrientdeficient) and nonligninolytic (nutrient-rich) culture conditions. Rapid metabolism of this chlorinated pesticide occurred under each nutrient condition tested. However, the extent of degradation and the nature of the metabolic products differed for nutrient-deficient and nutrient-rich media. The pathways for endosulfan metabolism were characterized by analysis of the fungal metabolites produced. The major endosulfan metabolites were identified by gas chromatography-electron capture detection and gas chromatography-mass spectrometry as endosulfan sulfate, endosulfan diol, endosulfan hydroxyether, and a unknown metabolite tentatively identified as endosulfan dialdehyde. The nature of the metabolites formed indicates that this organism utilizes both oxidative and hydrolytic pathways for metabolism of this pesticide. Piperonyl butoxide, a known cytochrome P-450 inhibitor, significantly inhibited the oxidation of endosulfan to endosulfan sulfate and enhanced hydrolysis of endosulfan to endosulfan diol. We suggest that the metabolism of endosulfan is mediated by two divergent pathways, one hydrolytic and the other oxidative. Judging by the inactivity of extracellular fluid and partially purified lignin peroxidase in metabolizing endosulfan, we conclude that metabolism of this compound does not involve the action of extracellular peroxidases.
Epidemiological data and in vivo animal experiments have indicated that exposure to the Ah-receptor (AhR) ligand dioxin and other dioxin-like compounds can lead to cardiovascular toxicity and atherosclerosis. Here, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand, on the differentiation of U937 cells into foam cells, which are considered to be early lesions of atherosclerosis. Our findings show that, like oxidized low-density lipoprotein (oxLDL), TCDD promotes the differentiation of U937 macrophages to atherogenic foam cells, verified by lipid accumulation and extensive formation of blebs on the cell surface, which are characteristics of foam cells. Through screening expression patterns of typical genes involved in atherosclerosis and foam cell generation, we could demonstrate that mRNA levels of cyclooxygenase-2, interleukin 1beta, and tumor necrosis factor-alpha were increased in a time- and dose-dependent manner in U937 macrophages treated with TCDD, like oxLDL, and that these changes accompanied significantly elevated levels of matrix-degrading metalloproteinases (MMP)-1, MMP-3, MMP-12, and MMP-13. Increased levels of MMPs were associated with TCDD-stimulated cell migration of U937 macrophages. These findings clearly indicate that AhR ligands, like TCDD, stimulate differentiation of U937 macrophages into potentially plaque-forming foam cells.
Evidence has been obtained to indicate that cyclodiene-type insecticides, e.g., heptachlor epoxide and gamma-BHC, mimic the action of picrotoxinin. These insecticides inhibit the GABA (gamma-aminobutyric acid)-stimulated chloride uptake in the coxal muscle of the American cockroach, and directly compete against [3H]a-dihydropicrotoxinin for binding in the rat brain synaptosomes. Moreover, several cyclodiene-resistant insect strains are also resistant to picrotoxinin. This cross-resistance is specific to picrotoxinin and does not extend to other neuroexcitants. These insecticides, like picrotoxinin, cause central nerve excitation by stimulating transmitter release. Similarity in molecular structures also has been pointed out. These results indicate that some of the nerve excitation symptoms that insecticides cause are likely due to their interaction with picrotoxinin receptor.
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