Dataset Information

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases.During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR.These data reveal that leflunomide, an anti-inflammatory drug, is an agonist of the AhR. Our findings link AhR activation by leflunomide to inhibition of fin regeneration in zebrafish. Identification of alternative AhR agonists is a critical step in evaluating the AhR as a therapeutic target for the treatment of immune disorders.

SUBMITTER: O'Donnell EF

PROVIDER: S-EPMC2948512 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

O'Donnell Edmond F EF Saili Katerine S KS Koch Daniel C DC Kopparapu Prasad R PR Farrer David D Bisson William H WH Mathew Lijoy K LK Sengupta Sumitra S Kerkvliet Nancy I NI Tanguay Robert L RL Kolluri Siva Kumar SK

PloS one 20101001 10

<h4>Background</h4>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases.<h4>Methodology/principal findings</h4>During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory dru ...[more]

PMID: 20957046

Similar Datasets

Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, the role of the AHR in normal physiology is still an area of intense investigation. For example, this receptor plays an important role in certain immune responses. We have previously determined that the AHR can mediate repression of acute-phase genes in the liver. For this observation to be therapeutically useful, selective activation of the AHR would likely be necessary. Recently, the selective estrogen receptor ligand WAY-169916 has also been shown to be a selective AHR ligand. WAY-169916 can efficiently repress cytokine-mediated acute-phase gene expression (e.g., SAA1) yet fail to mediate a dioxin response element-driven increase in transcriptional activity. The goals of this study were to structurally modify WAY-169916 to block binding to the estrogen receptor and increase its affinity for the AHR. A number of WAY-169916 derivatives were synthesized and subjected to characterization as AHR ligands. The substitution of a key hydroxy group for a methoxy group ablates binding to the estrogen receptor and increases its affinity for the AHR. The compound 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA 360), in particular, exhibited essentially no AHR agonist activity yet was able to repress cytokine-mediated SAA1 gene expression in Huh7 cells. SGA 360 was tested in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated ear inflammatory edema model using C57BL6/J and Ahr(-/-) mice. Our findings indicate that SGA 360 significantly inhibits TPA-mediated ear swelling and induction of a number of inflammatory genes (e.g., Saa3, Cox2, and Il6) in C57BL6/J mice. In contrast, SGA 360 had no effect on TPA-mediated ear swelling or inflammatory gene expression in Ahr(-/-) mice. Collectively, these results indicate that SGA 360 is a selective Ah receptor modulator (SAhRM) that exhibits anti-inflammatory properties in vivo.

Project description:BackgroundMultiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE).MethodsAn in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE.ResultsMolecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA.ConclusionOur findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS.

Dataset Information

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

Publications

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets