The overall goal of this proposal is to identify the regulatory role of the aryl hydrocarbon receptor (AhR) interacting with NF-?B signaling in controlling function and differentiation of dendritic cells (DC). Alteration of cellular communication of DC with T cells can lead to immunological disorders like autoimmune diseases, allergy and immunodeficiency. Especially interaction of the AhR with NF-?B RelB mediated pathways critical for appropriate immune responses will be the focus of this study. DCs are key regulator of immunity or tolerance, and the NF-?B members RelA and RelB are critical for the development, differentiation and function of DC. Therefore, the AhR may interact with NF-?B Rel proteins to regulate the function of DCs, which affects T cell differentiation in particular pathological conditions mediated by activation of NF-?B and AhR. This study can provide a definite link and mechanism between the exposure to persistent organic pollutants like dioxin and dioxin-like compounds activating the AhR and the development of diseases based on their immunotoxic effects. This will allow for more clearly defined endpoints to assess the effects of AhR activating compounds and may also provide opportunities to develop new substances that can then be used to manipulate the immune system and allow for effective preventative measures to be implemented.

Public Health Relevance

The present study focuses on a novel concept of the function of aryl hydrocarbon receptor (AhR) in cross-talk with NF-?B signaling pathways important for the understanding how the transcriptional potential and activity of the AhR is implemented in the differentiation and function of dendritic cells in the immune system. The current study is critical in understanding the potential biological function of the AhR in the immune system and its role in immunological disorders like allergy or autoimmune disease. This work will help to understand the mechanism how environmental toxicants like dioxin or dioxin-like compounds, which activate the AhR, affect critical functions of the immune system and human health.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Chadwick, Lisa
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University of California Davis
Public Health & Prev Medicine
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Kado, Sarah; Chang, W L William; Chi, Aimy Nguyen et al. (2017) Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells. Arch Toxicol 91:2209-2221
Vogel, Christoph F A; Haarmann-Stemmann, Thomas (2017) The aryl hydrocarbon receptor repressor - More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer. Curr Opin Toxicol 2:109-119
Vogel, Christoph F A; Charrier, Jessica G; Wu, Dalei et al. (2016) Physicochemical properties of iron oxide nanoparticles that contribute to cellular ROS-dependent signaling and acellular production of hydroxyl radical. Free Radic Res 50:1153-1164
Vogel, Christoph F A; Chang, W L William; Kado, Sarah et al. (2016) Transgenic Overexpression of Aryl Hydrocarbon Receptor Repressor (AhRR) and AhR-Mediated Induction of CYP1A1, Cytokines, and Acute Toxicity. Environ Health Perspect 124:1071-83
Bekki, Kanae; Vogel, Helena; Li, Wen et al. (2015) The aryl hydrocarbon receptor (AhR) mediates resistance to apoptosis induced in breast cancer cells. Pestic Biochem Physiol 120:5-13
Tigges, Julia; Haarmann-Stemmann, Thomas; Vogel, Christoph F A et al. (2014) The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction. J Invest Dermatol 134:556-559
Vogel, Christoph F A; Khan, Elaine M; Leung, Patrick S C et al. (2014) Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-?B. J Biol Chem 289:1866-75
Chan, Jackie K W; Vogel, Christoph F; Baek, Jaeeun et al. (2013) Combustion derived ultrafine particles induce cytochrome P-450 expression in specific lung compartments in the developing neonatal and adult rat. Am J Physiol Lung Cell Mol Physiol 304:L665-77
Vogel, Christoph F A; Wu, Dalei; Goth, Samuel R et al. (2013) Aryl hydrocarbon receptor signaling regulates NF-?B RelB activation during dendritic-cell differentiation. Immunol Cell Biol 91:568-75
Chan, Jackie K W; Charrier, Jessica G; Kodani, Sean D et al. (2013) Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs. Part Fibre Toxicol 10:34

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