Document Detail


Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
MedLine Citation:
PMID:  23348739     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild-type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD.
Authors:
Ellen H van den Bogaard; Judith G M Bergboer; Mieke Vonk-Bergers; Ivonne M J J van Vlijmen-Willems; Stanleyson V Hato; Pieter G M van der Valk; Jens Michael Schröder; Irma Joosten; Patrick L J M Zeeuwen; Joost Schalkwijk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  917-27     Citation Subset:  AIM; IM    
Affiliation:
Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands. e.vandenbogaard@derma.umcn.nl
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MeSH Terms
Descriptor/Qualifier:
Administration, Topical
Cell Differentiation / drug effects
Cells, Cultured
Coal Tar / administration & dosage*
Cytokines / metabolism
Dermatitis, Atopic / drug therapy*,  immunology,  pathology,  physiopathology*
Humans
Intermediate Filament Proteins / genetics,  metabolism
Keratinocytes / drug effects,  pathology,  physiology
Models, Biological
NF-E2-Related Factor 2 / metabolism
Oxidative Stress / drug effects
RNA, Small Interfering / genetics
Receptors, Aryl Hydrocarbon / antagonists & inhibitors,  drug effects*,  genetics,  physiology*
Signal Transduction / drug effects
Th2 Cells / immunology
Up-Regulation / drug effects
Chemical
Reg. No./Substance:
0/Cytokines; 0/Intermediate Filament Proteins; 0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/RNA, Small Interfering; 0/Receptors, Aryl Hydrocarbon; 0/filaggrin; 8007-45-2/Coal Tar
Comments/Corrections
Comment In:
J Clin Invest. 2013 Feb 1;123(2):551-3   [PMID:  23348733 ]

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