This proposal investigates a new mechanism of cross talk between the transcription factors Aryl hydrocarbon Receptor (AhR) and the NF-?B member RelB in the process of dendritic cell (DC) differentiation. The long-term objective of the project is to give insight into the missing knowledge about the endogenous role of the AhR and its role together with RelB in regulating gene transcription especially immune regulatory genes like cytokines and chemokines. The major impetus for this study has been provided by recent findings that RelB, a member of the NF-?B family, may play an important role in the classical AhR signaling pathway. In the present study, we will assess the physiological relevance of the AhR/RelB activity in human DC in vitro systems for the process of DC differentiation. We like to evaluate the established human myeloid cell lines U937 and THP-1 as a source of DC-like cells since most if not all studies with DC and dioxin have been performed in mice or cells derived from mouse. Further, we like to test the effect of TCDD (AhR agonist) and AhR antagonists on differentiation and the biological response of the DCs based on the measurement of selected activation markers such as surface expression of CD1a, CD40, CD80, CD86 and MHCII by flow cytometry and chemokines relevant for the function of DCs like DC-CK1, DC-STAMP, and IL-8 mRNA expression by real time PCR analysis. In project 2 of the current proposal we will identify the role of AhR and AhR/RelB activity in the differentiation process of bone marrow cells derived from C57BL/6 wild type and AhR null (AhR-/-) mice into DC. This study reveals a novel concept of the function of the AhR together with RelB and is critical in understanding how environmental toxicants like dioxins affect critical functions of the immune system and human health.

Public Health Relevance

About 15 years ago Hankinson and coworkers identified the encoded protein ARNT, which is required for ligand-dependent translocation of the Aryl hydrocarbon Receptor (AhR) to the nucleus and its binding to Dioxin responsive elements (DRE) mediating induction of xenobiotic metabolizing enzymes (classical AhR/ARNT pathway), but the physiological role of the AhR remains a key question. The present study focuses on a new mechanism of cross talk between AhR and the NF- ?B member RelB (alternative AhR/RelB pathway), which suggests an example of how an activated AhR pathway may connect to the NF-?B subunit RelB in order to cooperatively regulate cytokine/chemokine expression as well as differentiation and function of dendritic cells. This work will help to understand the mechanism how environmental toxicants like dioxin or dioxin-like compounds, which activate the AhR, elicit immunotoxic effects and lead to adverse health effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES015846-01A2
Application #
7740312
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Chadwick, Lisa
Project Start
2009-07-16
Project End
2011-06-30
Budget Start
2009-07-16
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$219,960
Indirect Cost
Name
University of California Davis
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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
Wu, Dalei; Nishimura, Noriko; Kuo, Victoria et al. (2011) Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice. Arterioscler Thromb Vasc Biol 31:1260-7
Dong, Bin; Cheng, Wei; Li, Wen et al. (2011) FRET analysis of protein tyrosine kinase c-Src activation mediated via aryl hydrocarbon receptor. Biochim Biophys Acta 1810:427-31
Vogel, Christoph Franz Adam; Li, Wen; Wu, Dalei et al. (2011) Interaction of aryl hydrocarbon receptor and NF-?B subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch Biochem Biophys 512:78-86
Wu, Dalei; Li, Wen; Lok, Patty et al. (2011) AhR deficiency impairs expression of LPS-induced inflammatory genes in mice. Biochem Biophys Res Commun 410:358-63
Sciullo, Eric M; Vogel, Christoph F; Wu, Dalei et al. (2010) Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p'-DDT in U937 macrophages. Arch Toxicol 84:957-66
Li, Wen; Vogel, Christoph F A; Wu, Dalei et al. (2010) Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice. Biol Chem 391:1205-19
Vogel, Christoph F A; Matsumura, Fumio (2009) A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol 77:734-45
Sciullo, Eric M; Dong, Bin; Vogel, Chris F A et al. (2009) Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages. Chemosphere 74:1531-7
Vogel, Christoph F A; Goth, Samuel R; Dong, Bin et al. (2008) Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 375:331-5