Abstract
BackgroundThe 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.Methodology/Principal FindingsDuring 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.ConclusionsThese 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.
Highlights
The aryl hydrocarbon receptor (AhR) is a member of the PerAhR/AhR Nuclear Translocator (Arnt)-Sim (PAS) family of proteins
The AhR is a cytosolic transcription factor that, in its latent unliganded state, forms complexes with HSP90 and XAP2.[1]. Upon ligand binding, the AhR translocates to the nucleus, where it complexes with its heterodimerization partner, the AhR Nuclear Translocator (Arnt), to modulate expression of AhR target genes containing functional xenobiotic response elements (XREs).[1]
Despite the negative physiological effects associated with TCDD activation of AhR in vivo, recent studies on the AhR suggest that this receptor may play a role in the control of tumor progression in the absence of exogenous compounds and further, that modulators of the AhR may be useful as therapeutics for immune-mediated diseases and cancer.[12,13,14,15,16]
Summary
The aryl hydrocarbon receptor (AhR) is a member of the PerAhR/Arnt-Sim (PAS) family of proteins. [4,5,6] Further, the AhR has been shown to modulate cell cycle progression and cellular differentiation independent of TCDD.[7] In addition, the AhR can modulate tissue regeneration pathways in vivo.[8,9] The AhR can induce mitogen-activated protein kinases as well as modulate function of tyrosine kinases.[10,11] Despite the negative physiological effects associated with TCDD activation of AhR in vivo, recent studies on the AhR suggest that this receptor may play a role in the control of tumor progression in the absence of exogenous compounds and further, that modulators of the AhR may be useful as therapeutics for immune-mediated diseases and cancer.[12,13,14,15,16]. 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
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