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Functional and phenotypic effects of AhR activation in inflammatory dendritic cells.

ABSTRACT: Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immune suppression. Dendritic cells (DCs) are key antigen presenting cells governing T cell activation and differentiation. However, the consequences of AhR activation in DCs are not fully defined. We hypothesized that AhR activation alters DC differentiation and generates dysfunctional DCs. To test this hypothesis, inflammatory bone marrow-derived DCs (BMDCs) from C57Bl/6 mice were generated in the presence of vehicle or TCDD. TCDD decreased CD11c expression but increased MHC class II, CD86 and CD25 expression on the BMDCs. The effects of TCDD were strictly AhR-dependent but not exclusively DRE-mediated. Similar effects were observed with two natural AhR ligands, 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid (ITE). TCDD increased LPS- and CpG-induced IL-6 and TNF-alpha production by BMDCs but decreased their NO production. TCDD decreased CpG-induced IL-12p70 production by BMDCs but did not affect their secretion of IL-10. TCDD downregulated LPS- and CpG-induced NF-kB p65 levels and induced a trend towards upregulation of RelB levels in the BMDCs. AhR activation by TCDD modulated BMDC uptake of both soluble and particulate antigens. Induction of indoleamine-2,3-dioxygenase (IDO) and TGF-beta3 has been implicated in the generation of regulatory T cells following AhR activation. TCDD increased IDO1, IDO2 and TGF-beta3 mRNA levels in BMDCs as compared to vehicle. Despite the induction of regulatory mediators, TCDD-treated BMDCs failed to suppress antigen-specific T cell activation. Thus, AhR activation can directly alter the differentiation and innate functions of inflammatory DCs without affecting their ability to successfully interact with T cells.

SUBMITTER: Bankoti J

PROVIDER: S-EPMC2885531 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Functional and phenotypic effects of AhR activation in inflammatory dendritic cells.

Bankoti Jaishree J Rase Ben B Simones Tom T Shepherd David M DM

Toxicology and applied pharmacology 20100327 1-2

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immune suppression. Dendritic cells (DCs) are key antigen presenting cells governing T cell activation and differentiation. However, the consequences of AhR activation in DCs are not fully defined. We hypothesized that AhR activation alters DC differentiation and generates dysfunctional DCs. To test this hypothesis, inflammatory bone marrow-derived DCs (BMDCs) from C57Bl/6 mice were generated in the ...[more]

PMID: 20350561

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Project description:Pulmonary fibrosis, a chronic lung disease caused by progressive deterioration of lung tissue, is generated by several factors including genetic and environmental ones. In response to long-term exposure to environmental stimuli, aberrant tissue repair and epithelial cell-to- mesenchymal cell transition (EMT) trigger the subsequent progression of pulmonary fibrotic diseases. The Aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by ligands providing lung dysfunction when activated by environmental toxins, such as polycyclic aromatic hydrocarbons. Our previous study demonstrated that AhR mediates α-SMA expression by directly binding to the α-SMA (fibroblast differentiation marker) promoter, suggesting the role of AhR in mediating fibrogenic progression. Here we follow the hypothesis that macrophage infiltrated microenvironments may trigger inflammation and subsequent fibrosis. We studied the expression of cytokines in RAW 264.7 cells by AhR activation through an ELISA assay. To investigate molecular events, migration, western blotting and zymography assays were carried out. We found that AhR agonists such as TCDD, IP and FICZ, promote the migration and induce inflammatory mediators such as TNF-α and G-CSF, MIP-1α, MIP-1β and MIP-2. These cytokines arbitrate EMT marker expression such as E-cadherin, fibronectin, and vimentin in pulmonary epithelial cells. Expression of proteins of MMPs in mouse macrophages was determined by zymography, showing the caseinolytic activity of MMP-1 and the gelatinolytic action of MMP-2 and MMP-9. Taken together, the present study showed that AhR activated macrophages create an inflammatory microenvironment which favours the fibrotic progression of pulmonary epithelial cells. Such production of inflammatory factors was accomplished by affecting the Wnt/β-catenin signalling pathway, thereby creating a microenvironment which enhances the epithelial-mesenchymal transition, leading to fibrosis of the lung.

Project description:During silicosis, immune cells, including macrophages, T cells, B cells, and NK cells, participate in fibrosis development through alteration of the immune status. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with a key role in initiating immune responses and sustaining immune tolerance to maintain homeostasis. The relative contribution of DCs to silicosis progression is not well-documented. In the current study, we investigated the phenotypic and functional alterations of peripheral blood mononuclear cell (PBMC)-derived DCs of Sprague-Dawley (SD) rat during immune responses to silica exposure. We established models for direct and indirect exposure of DCs to silica by either treating DCs with silica or coculturing them with alveolar macrophages (AMs) treated with silica, respectively. The functional activity of DCs was analyzed by measuring their expression of costimulatory molecules, fluorescent microparticle uptake, cytokine production, and ability to mediate T cell polarization in vitro. In vivo, we demonstrated that silica could induce DC migration in response to silica exposure. Our results show that cytokine production by DCs was increased in response to direct silica direct exposure, while indirect silica exposure led to reduced cytokine levels. Moreover, the phagocytic capacity of DCs increased in cocultures after silica exposure. Gene and protein expression analyses showed that silica exposure altered the expression levels of Toll-like receptor pathway proteins and inflammatory factors. DC surface expression of the costimulatory molecules, CD80, CD86, and major histocompatibility complex, was inhibited by exposure to silica, which mediated a Th2-polarizing response in vitro. In rats, silica exposure induced migration of DCs from the peripheral blood into the alveoli. These results demonstrate that direct and indirect exposure to silica particles alter the phenotype and function of DCs, thereby regulating immune responses. Such changes may contribute to the development of silicosis by altering DC phenotype, function, and migration and by influencing the balance between Th1 and Th2 cells.

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Functional and phenotypic effects of AhR activation in inflammatory dendritic cells.

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Functional and phenotypic effects of AhR activation in inflammatory dendritic cells.

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