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Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.
J Clin Invest 2013; 123(2):917-27JCI

Abstract

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+Show Affiliations

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.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23348739

Citation

van den Bogaard, Ellen H., et al. "Coal Tar Induces AHR-dependent Skin Barrier Repair in Atopic Dermatitis." The Journal of Clinical Investigation, vol. 123, no. 2, 2013, pp. 917-27.
van den Bogaard EH, Bergboer JG, Vonk-Bergers M, et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013;123(2):917-27.
van den Bogaard, E. H., Bergboer, J. G., Vonk-Bergers, M., van Vlijmen-Willems, I. M., Hato, S. V., van der Valk, P. G., ... Schalkwijk, J. (2013). Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. The Journal of Clinical Investigation, 123(2), pp. 917-27. doi:10.1172/JCI65642.
van den Bogaard EH, et al. Coal Tar Induces AHR-dependent Skin Barrier Repair in Atopic Dermatitis. J Clin Invest. 2013;123(2):917-27. PubMed PMID: 23348739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. AU - van den Bogaard,Ellen H, AU - Bergboer,Judith G M, AU - Vonk-Bergers,Mieke, AU - van Vlijmen-Willems,Ivonne M J J, AU - Hato,Stanleyson V, AU - van der Valk,Pieter G M, AU - Schröder,Jens Michael, AU - Joosten,Irma, AU - Zeeuwen,Patrick L J M, AU - Schalkwijk,Joost, Y1 - 2013/01/25/ PY - 2012/07/05/received PY - 2012/10/18/accepted PY - 2013/1/26/entrez PY - 2013/1/26/pubmed PY - 2013/5/15/medline SP - 917 EP - 27 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 123 IS - 2 N2 - 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/23348739/Coal_tar_induces_AHR_dependent_skin_barrier_repair_in_atopic_dermatitis_ DB - PRIME DP - Unbound Medicine ER -