Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

Lawrence, B. Paige; Denison, Michael S.; Novak, Hermann; Vorderstrasse, Beth A.; Harrer, Nathalie; Neruda, Wolfgang; Reichel, Claudia; Woisetschläger, Maximilian

doi:10.1182/blood-2007-08-109645

Cited by 98 publications

(76 citation statements)

References 41 publications

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“…AhR activation induces regulatory T cell differentiation (45) and forms a complex with Stat1 and NF-kB in macrophages (46) and then modulates inflammatory responses. Recent reports suggest that AhR plays an essential role in the anti-inflammatory effect of other compounds (46,47). Because quercetin is a ligand of AhR and DCs express high levels of AhR (48), it is likely that AhR may mediate the suppressive effect of quercetin on DCs.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive Effect of Quercetin on Dendritic Cell Activation and Function

Huang

Cheng

et al. 2010

The Journal of Immunology

173

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Section: Discussionmentioning

confidence: 99%

Immunosuppressive Effect of Quercetin on Dendritic Cell Activation and Function

Huang

Cheng

et al. 2010

The Journal of Immunology

173

120

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“…The newly identified AhR agonist VAF347 was described as a potent immunosuppressive compound in a murine model of T celldependent allergic asthma (11,12). This effect was likely mediated via impaired DC function, rather than by direct impairment of T cells (12).…”

Section: Discussionmentioning

confidence: 99%

“…The low m.w. compound VAF347 represents a recently identified AhR ligand with potent anti-inflammatory activity (11). VAF347 exceeded suplatast tosilate, a commonly used anti-asthma drug, in suppressing lung inflammation in a murine model of allergic asthma, an effect mediated at least in part via altered dendritic cell (DC) function (12).…”

mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Inhibits In Vitro Differentiation of Human Monocytes and Langerhans Dendritic Cells

Platzer

Richter

Kneidinger

et al. 2009

The Journal of Immunology

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The transcription factor aryl hydrocarbon receptor (AhR) represents a promising therapeutic target in allergy and autoimmunity. AhR signaling induced by the newly described ligand VAF347 inhibits allergic lung inflammation as well as suppresses pancreatic islet allograft rejection. These effects are likely mediated via alterations in dendritic cell (DC) function. Moreover, VAF347 induces tolerogenic DCs. Langerhans cells (LCs) are immediate targets of exogenous AhR ligands at epithelial surfaces; how they respond to AhR ligands remained undefined. We studied AhR expression and function in human LCs and myelopoietic cell subsets using a lineage differentiation and gene transduction model of human CD34+ hematopoietic progenitors. We found that AhR is highly regulated during myeloid subset differentiation. LCs expressed highest AhR levels followed by monocytes. Conversely, neutrophil granulocytes lacked AhR expression. AhR ligands including VAF347 arrested the differentiation of monocytes and LCs at an early precursor cell stage, whereas progenitor cell expansion or granulopoiesis remained unimpaired. AhR expression was coregulated with the transcription factor PU.1 during myeloid subset differentiation. VAF347 inhibited PU.1 induction during initial monocytic differentiation, and ectopic PU.1 restored monocyte and LC generation in the presence of this compound. AhR ligands failed to interfere with cytokine receptor signaling during LC differentiation and failed to impair LC activation/maturation. VAF347-mediated antiproliferative effect on precursors undergoing LC lineage differentiation occurred in a clinically applicable serum-free culture model and was not accompanied by apoptosis induction. In conclusion, AhR agonist signaling interferes with transcriptional processes leading to monocyte/DC lineage commitment of human myeloid progenitor cells.

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“…Moreover, in response to lipopolisaccaride, AhR-deficient macrophages produced increased proinflammatory cytokines, and AhR-deficient DCs secreted less anti-inflammatory cytokine IL-10 (10). In another study, bone marrow-derived DCs stimulated with a synthetic AhR ligand, VAF347, were found to produce less IL-6, an effect that was suppressed in AhRdeficient DCs (20). These studies suggest that AhR in these cells may use a "noncanonical" (ARNT-independent) pathway instead of the canonical (ARNT-mediated) pathway, possibly through the recruitment of nuclear factor-jB family members (1).…”

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confidence: 94%