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, Maximilian Woisetschlager

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleu-kin (IL)-6, CD86, and human leukocyte antigen (HLA)-DR expression by human monocyte-derived DC, 3 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 biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpres-sion of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) 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.

Original languageEnglish (US)
Pages (from-to)1158-1165
Number of pages8
JournalBlood
Volume112
Issue number4
DOIs
StatePublished - Aug 15 2008

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Lawrence, B. P., Denison, M. S., Novak, H., Vorderstrasse, B. A., Harrer, N., Neruda, W., Reichel, C., & Woisetschlager, M. (2008). Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood, 112(4), 1158-1165. https://doi.org/10.1182/blood-2007-08-109645