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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1158-1165. Prepublished online as a Blood First Edition Paper on February 12, 2008; DOI 10.1182/blood-2007-08-109645. This Article Full Text (PDF) All Versions of this Article: blood-2007-08-109645v1 112/4/1158    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lawrence, B. P. Articles by Woisetschlager, M. Search for Related Content PubMed PubMed Citation Articles by Lawrence, B. P. Articles by Woisetschlager, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 28, 2007 Accepted January 6, 2008 Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low molecular weight compound B. Paige Lawrence, Michael S Denison, Hermann Novak, Beth A Vorderstrasse, Nathalie Harrer, Wolfgang Neruda, Claudia Reichel, and Maximilian Woisetschlager* Department of Environmental Medicine, University of Rochester, Rochester, NY, United States Department of Environmental Toxicology, University of California, Davis, CA, United States Department of Autoimmunity and Transplantation, Novartis Institute for Biomedical Research Vienna, Vienna, Austria Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, United States * Corresponding author; email: maximilian.woisetschlaeger{at}novartis.com. VAF347 is a low molecular weight compound which inhibits allergic lung inflammation in vivo. This effect is likely due to a block of dendritic cell (DC) function to generate pro-inflammatory T-helper (Th) cells since VAF347 inhibits IL-6, CD86 and HLA-DR expression by human monocyte derived DC, three relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biological activity of VAF347 since, i) other AhR agonists display an identical activity profile in vitro, ii) gene silencing of wild type AhR expression or forced over-expression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line and iii) AhR deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Ah receptor: xenobiotic response meets inflammation Qiang Ma Blood 2008 112: 928-929. [Full Text] [PDF] This article has been cited by other articles: S. Zhang, P. Lei, X. Liu, X. Li, K. Walker, L. Kotha, C. Rowlands, and S. Safe The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy Endocr. Relat. Cancer, September 1, 2009; 16(3): 835 - 844. [Abstract] [Full Text] [PDF] B. Platzer, S. Richter, D. Kneidinger, D. Waltenberger, M. Woisetschlager, and H. Strobl Aryl Hydrocarbon Receptor Activation Inhibits In Vitro Differentiation of Human Monocytes and Langerhans Dendritic Cells J. Immunol., July 1, 2009; 183(1): 66 - 74. [Abstract] [Full Text] [PDF] B. Jux, S. Kadow, and C. Esser Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice J. Immunol., June 1, 2009; 182(11): 6709 - 6717. [Abstract] [Full Text] [PDF] E. Hauben, S. Gregori, E. Draghici, B. Migliavacca, S. Olivieri, M. Woisetschlager, and M. G. Roncarolo Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells Blood, August 15, 2008; 112(4): 1214 - 1222. [Abstract] [Full Text] [PDF]

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