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Vogel C.F.A.,University of California at Davis | Khan E.M.,University of California at Davis | Leung P.S.C.,University of California at Davis | Gershwin M.E.,University of California at Davis | And 5 more authors.
Journal of Biological Chemistry | Year: 2014

The aryl hydrocarbon receptor (AhR) is involved in the regulation of immune responses, T-cell differentiation, and immunity. Here, we show that inflammatory stimuli such as LPS induce the expression of AhR in human dendritic cells (DC) associated with an AhR-dependent increase of CYP1A1 (cytochrome P4501A1). In vivo data confirmed the elevated expression of AhR by LPS and the LPS-enhanced 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of CYP1A1 in thymus of B6 mice. Inhibition of nuclear factor-κB (NF-κB) repressed both normal and LPS-enhanced, TCDD-inducible, AhR-dependent gene expression and canonical pathway control of RelA-regulated AhR-responsive gene expression. LPS-mediated induction of AhR was NF-κB-dependent, as shown in mouse embryonic fibroblasts (MEFs) derived from Rel null mice. AhR expression and TCDD-mediated induction of CYP1A1 was significantly reduced in RelA-deficient MEF compared with wild type MEF cells and ectopic expression of RelA restored the expression of AhR and induction of CYP1A1 in MEF RelA null cells. Promoter analysis of the human AhR gene identified three putative NF-κB-binding elements upstream of the transcription start site. Mutation analysis of the AhR promoter identified one NF-κB site as responsible for mediating the induction of AhR expression by LPS and electrophoretic shift assays demonstrated that this NF-κB motif is recognized by the RelA/p50 heterodimer. Our results show for the first time that NF-κB RelA is a critical component regulating the expression of AhR and the induction of AhR-dependent gene expression in immune cells illustrating the interaction of AhR and NF-κB signaling. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Esser C.,Leibniz Research Institute for Environmental Medicine | Rannug A.,Karolinska Institutet
Pharmacological Reviews | Year: 2015

The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim–basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views—namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Theologidis I.,Instituto Gulbenkian Of Ciencia | Theologidis I.,Benaki Phytopathological Institute | Chelo I.M.,Instituto Gulbenkian Of Ciencia | Goy C.,Instituto Gulbenkian Of Ciencia | And 3 more authors.
BMC Biology | Year: 2014

Background: Evolutionary transitions from outcrossing between individuals to selfing are partly responsible for the great diversity of animal and plant reproduction systems. The hypothesis of 'reproductive assurance' suggests that transitions to selfing occur because selfers that are able to reproduce on their own ensure the persistence of populations in environments where mates or pollination agents are unavailable. Here we test this hypothesis by performing experimental evolution in Caenorhabditis elegans. Results: We show that self-compatible hermaphrodites provide reproductive assurance to a male-female population facing a novel environment where outcrossing is limiting. Invasions of hermaphrodites in male-female populations, and subsequent experimental evolution in the novel environment, led to successful transitions to selfing and adaptation. Adaptation was not due to the loss of males during transitions, as shown by evolution experiments in exclusively hermaphroditic populations and in male-hermaphrodite populations. Instead, adaptation was due to the displacement of females by hermaphrodites. Genotyping of single-nucleotide polymorphisms further indicated that the observed evolution of selfing rates was not due to selection of standing genetic diversity. Finally, numerical modelling and evolution experiments in male-female populations demonstrate that the improvement of male fitness components may diminish the opportunity for reproductive assurance. Conclusions: Our findings support the hypothesis that reproductive assurance can drive the transition from outcrossing to selfing, and further suggest that the success of transitions to selfing hinges on adaptation of obligate outcrossing populations to the environment where outcrossing was once a limiting factor. © 2014 Theologidis et al.

Mayerl S.,Leibniz Institute for Age Research | Muller J.,Leibniz Institute for Age Research | Bauer R.,Friedrich - Schiller University of Jena | Richert S.,Max Planck Institute for Experimental Medicine | And 7 more authors.
Journal of Clinical Investigation | Year: 2014

Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

Marini A.,Leibniz Research Institute for Environmental Medicine | Reinelt K.,Bitop AG | Krutmann J.,Leibniz Research Institute for Environmental Medicine | Bilstein A.,Bitop AG
Skin Pharmacology and Physiology | Year: 2014

Introduction: The natural cyclic tetrahydropyrimidine, ectoine, is a low-molecular, water-binding, organic osmolyte. Previously, topical application of ectoine to healthy human skin was shown to improve skin hydration as well as skin barrier function. Objectives: We therefore speculated that topical application of ectoine would be beneficial for patients with atopic dermatitis (AD), in which a genetically defined defect in skin barrier function is of major pathogenetic relevance. We assessed the efficacy of an ectoine-containing cream (EHK02-01) in the management of 65 patients with mild to moderate AD in a randomized, intra-individual, double-blind, multi-center trial, in which the efficacy of ectoine was compared to a nonsteroidal anti-inflammatory cream previously found to primarily act on skin barrier function and therefore with a comparable mode of action. Methods: Sixty-five patients with mild to moderate AD aged 18-65 years were enrolled. The patients applied EHK02-01 and the control cream on two symmetrical lesions twice daily for 28 days. At the beginning, after 7 and after 28 days, treated skin areas were assessed by modified, objective local SCORAD (Scoring Atopic Dermatitis) and IGA (Investigator's Global Assessment) as well as the patients' judgment of efficacy and their assessment of pruritus. Results: EHK02-01 was found to be very well tolerated. Even more important, efficacy of EHK02-01 treatment was equivalent to that achieved with the reference product. Conclusion: These results indicate that topical treatment with EHK02-01 may represent a novel option for the treatment of patients with AD. Copyright © 2013 S. Karger AG, Basel.

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