Skip to main content

Advertisement

SpringerLink
Log in

Functions of the aryl hydrocarbon receptor in the skin

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Among other functions, the skin serves as the barrier against the environment and provides vital protection from physical or chemical harm and from infection. Skin cells express the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and sensor of environmental chemicals; at the same time, AHR ligands are abundant in skin from exogenous or endogenous sources. For example, solar radiation, in particular ultraviolet (UV) B, generates AHR ligands from tryptophan in the skin. Recent evidence has shown that AHR is involved in the (patho)physiology of skin including the regulation of skin pigmentation, photocarcinogenesis, and skin inflammation. We here provide a state-of-the-art summary of work which relates to the role of the AHR in (1) adaptive responses against environmental challenges such as UVB or topical chemicals and (2) intrinsic developmental roles for homeostasis of skin cells and (3) skin immunity. We also discuss the existing evidence that AHR antagonists or AHR ligands may be used for the prevention and/or treatment of skin disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Schmidt JV, Bradfield CA (1996) Ah receptor signaling pathways. Annu Rev Cell Dev Biol 12:55–89

    PubMed  CAS  Google Scholar 

  2. Dolwick KM, Schmidt JV, Carver LA, Swanson HI, Bradfield CA (1993) Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol 44(5):911–917

    PubMed  CAS  Google Scholar 

  3. Abel J, Haarmann-Stemmann T (2010) An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391(11):1235–1248

    PubMed  CAS  Google Scholar 

  4. Sun YV, Boverhof DR, Burgoon LD, Fielden MR, Zacharewski TR (2004) Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res 32(15):4512–4523

    PubMed  CAS  Google Scholar 

  5. Frericks M, Meissner M, Esser C (2007) Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes. Toxicol Appl Pharmacol 220(3):320–332

    PubMed  CAS  Google Scholar 

  6. Mitchell KA, Elferink CJ (2009) Timing is everything: consequences of transient and sustained AhR activity. Biochem Pharmacol 77(6):947–956

    PubMed  CAS  Google Scholar 

  7. Wu D, Li W, Lok P, Matsumura F, dam Vogel CF (2011) AhR deficiency impairs expression of LPS-induced inflammatory genes in mice. Biochem Biophys Res Commun 410(2):358–363

    PubMed  CAS  Google Scholar 

  8. Fritsche E, Schafer C, Calles C, Bernsmann T, Bernshausen T, Wurm M et al (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci USA 104(21):8851–8856

    PubMed  CAS  Google Scholar 

  9. Mimura J, Ema M, Sogawa K, Fujii-Kuriyama Y (1999) Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev 13(1):20–25

    PubMed  CAS  Google Scholar 

  10. Tigges J, Weighardt H, Wolff S, Gotz C, Forster I, Kohne Z, et al. (2012) Aryl Hydrocarbon Receptor Repressor (AhRR) function revisited: repression of CYP1 activity in human skin fibroblasts is not related to AhRR expression. J Invest Dermatol

  11. Romani N, Clausen BE, Stoitzner P (2010) Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol Rev 234(1):120–141

    PubMed  CAS  Google Scholar 

  12. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK et al (2006) The vast majority of CLA + T cells are resident in normal skin. J Immunol 176(7):4431–4439

    PubMed  CAS  Google Scholar 

  13. Nestle FO, Di MP, Qin JZ, Nickoloff BJ (2009) Skin immune sentinels in health and disease. Nat Rev Immunol 9(10):679–691

    PubMed  CAS  Google Scholar 

  14. Carlstedt-Duke JM (1979) Tissue distribution of the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Cancer Res 39(8):3172–3176

    PubMed  CAS  Google Scholar 

  15. Li W, Donat S, Dohr O, Unfried K, Abel J (1994) Ah receptor in different tissues of C57BL/6 J and DBA/2 J mice: use of competitive polymerase chain reaction to measure Ah-receptor mRNA expression. Arch Biochem Biophys 315(2):279–284

    PubMed  CAS  Google Scholar 

  16. Esser C (2012) The physiological role of AHR in the mouse immune system. In: Pojhanvirta R (ed) The AH receptor in biology and toxicology. Ref Type: Serial (Book,Monograph). Wiley&Sons, Hoboken, pp 499–510

    Google Scholar 

  17. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334

    PubMed  CAS  Google Scholar 

  18. Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1):102–116

    PubMed  CAS  Google Scholar 

  19. Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B (2011) Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci 124(1):1–22

    PubMed  CAS  Google Scholar 

  20. Rannug U, Rannug A, Sjoberg U, Li H, Westerholm R, Bergman J (1995) Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands. Chem Biol 2(12):841–845

    PubMed  CAS  Google Scholar 

  21. Rannug A, Rannug U, Rosenkranz HS, Winqvist L, Westerholm R, Agurell E et al (1987) Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. J Biol Chem 262(32):15422–15427

    PubMed  CAS  Google Scholar 

  22. Diani-Moore S, Labitzke E, Brown R, Garvin A, Wong L, Rifkind AB (2006) Sunlight generates multiple tryptophan photoproducts eliciting high-efficacy CYP1A induction in chick hepatocytes and in vivo. Toxicol Sci 90(1):96–110

    PubMed  CAS  Google Scholar 

  23. Wincent E, Amini N, Luecke S, Glatt H, Bergman J, Crescenzi C et al (2009) The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J Biol Chem 284(5):2690–2696

    PubMed  CAS  Google Scholar 

  24. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206(1):43–49

    PubMed  CAS  Google Scholar 

  25. Diani-Moore S, Ma Y, Labitzke E, Tao H, David WJ, Anderson J et al (2011) Discovery and biological characterization of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor activator generated by photoactivation of tryptophan by sunlight. Chem Biol Interact 193(2):119–128

    PubMed  CAS  Google Scholar 

  26. Hahn ME (2002) Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact 141(1–2):131–160

    PubMed  CAS  Google Scholar 

  27. Katiyar SK, Matsui MS, Mukhtar H (2000) Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1. J Invest Dermatol 114(2):328–333

    PubMed  CAS  Google Scholar 

  28. Ma Q, Lu AY (2007) CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. Drug Metab Dispos 35(7):1009–1016

    PubMed  CAS  Google Scholar 

  29. Modi BG, Neustadter J, Binda E, Lewis J, Filler RB, Roberts SJ et al (2012) Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. Science 335(6064):104–108

    PubMed  CAS  Google Scholar 

  30. Martin R, O’Shea J, Birnbaum LS, Luebke R (2008) Community corner. Striking the balance in multiple sclerosis. Nat Med 14(5):491

    PubMed  Google Scholar 

  31. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185(6):3190–3198

    PubMed  CAS  Google Scholar 

  32. Asp L, Johansson AS, Mann A, Owe-Larsson B, Urbanska EM, Kocki T et al (2011) Effects of proinflammatory cytokines on expression of kynurenine pathway enzymes in human dermal fibroblasts. J Inflamm (Lond) 8:25

    CAS  Google Scholar 

  33. Jux B, Kadow S, Esser C (2009) Langerhans cell maturation and contact hypersensitivity are impaired in aryl hydrocarbon receptor-null mice. J Immunol 182(11):6709–6717

    PubMed  CAS  Google Scholar 

  34. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K et al (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 107(46):19961–19966

    PubMed  CAS  Google Scholar 

  35. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–774

    PubMed  CAS  Google Scholar 

  36. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196(4):459–468

    PubMed  CAS  Google Scholar 

  37. Schallreuter KU, Salem MA, Gibbons NC, Maitland DJ, Marsch E, Elwary SM et al (2012) Blunted epidermal l-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: epidermal H2O2/ONOO(−)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling. FASEB J 26(6):2471–2485

    PubMed  CAS  Google Scholar 

  38. Wille G, Mayser P, Thoma W, Monsees T, Baumgart A, Schmitz HJ et al (2001) Malassezin–A novel agonist of the arylhydrocarbon receptor from the yeast Malassezia furfur. Bioorg Med Chem 9(4):955–960

    PubMed  CAS  Google Scholar 

  39. Vlachos C, Schulte BM, Magiatis P, Adema GJ, Gaitanis G (2012) Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit toll-like receptor-induced maturation in monocyte-derived dendritic cells. Br J Dermatol 167(3):496–505

    PubMed  CAS  Google Scholar 

  40. Gaitanis G, Velegraki A, Magiatis P, Pappas P, Bassukas ID (2011) Could Malassezia yeasts be implicated in skin carcinogenesis through the production of aryl-hydrocarbon receptor ligands? Med Hypotheses 77(1):47–51

    PubMed  CAS  Google Scholar 

  41. Jin UH, Lee SO, Safe S (2012) Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells. J Pharmacol Exp Ther 343(2):333–341

    PubMed  CAS  Google Scholar 

  42. Tiong CT, Chen C, Zhang SJ, Li J, Soshilov A, Denison MS et al (2012) A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERalpha protein. Carcinogenesis 33(5):1089–1097

    PubMed  CAS  Google Scholar 

  43. Caputo R, Monti M, Ermacora E, Carminati G, Gelmetti C, Gianotti R et al (1988) Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J Am Acad Dermatol 19(5 Pt 1):812–819

    PubMed  CAS  Google Scholar 

  44. Scholz A (2012) Karl Herxheimer - Geheimrat mit dem gelben Stern. J Dtsch Dermatol Ges 10(12):925–927

    Google Scholar 

  45. Passarini B, Infusino SD, Kasapi E (2010) Chloracne: still cause for concern. Dermatology 221(1):63–70

    PubMed  Google Scholar 

  46. Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, Fontao L et al (2012) The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci 125(1):310–317

    PubMed  CAS  Google Scholar 

  47. Gotz C, Pfeiffer R, Tigges J, Blatz V, Jackh C, Freytag EM et al (2012) Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: activating enzymes (Phase I). Exp Dermatol 21(5):358–363

    PubMed  Google Scholar 

  48. Kikuchi M (1984) Autopsy of patients with yusho. Prog Clin Biol Res 137:19–30

    PubMed  CAS  Google Scholar 

  49. Kanagawa Y, Matsumoto S, Koike S, Tajima B, Fukiwake N, Shibata S et al (2008) Association of clinical findings in Yusho patients with serum concentrations of polychlorinated biphenyls, polychlorinated quarterphenyls, and 2,3,4,7,8-pentachlorodibenzofuran more than 30 years after the poisoning event. Environ Health 7:47

    PubMed  Google Scholar 

  50. Masuda Y (1985) Health status of Japanese and Taiwanese after exposure to contaminated rice oil. Environ Health Perspect 60:321–325

    PubMed  CAS  Google Scholar 

  51. Hashiguchi I, Yoshimine Y, Maeda H, Gotou Y, Ishikawa M, Fujii S et al (2007) Epidemiologic examination on the prevalence of the periodontal diseases and oral pigmentation in Yusho patients in 2006. Fukuoka Igaku Zasshi 98(5):170–175

    PubMed  Google Scholar 

  52. Dunagin WG (1984) Cutaneous signs of systemic toxicity due to dioxins and related chemicals. J Am Acad Dermatol 10(4):688–700

    PubMed  CAS  Google Scholar 

  53. Jux B, Kadow S, Luecke S, Rannug A, Krutmann J, Esser C (2011) The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning. J Invest Dermatol 131(1):203–210

    PubMed  CAS  Google Scholar 

  54. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C et al (2011) Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. doi:10.1126/science.1214914

    Google Scholar 

  55. Luecke S, Backlund M, Jux B, Esser C, Krutmann J, Rannug A (2010) The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis. Pigment Cell Melanoma Res 23(6):828–833

    PubMed  CAS  Google Scholar 

  56. Wang XW, Li K, Guo S, Qiang HN, Liu L, Song P et al (2012) The association of functional polymorphisms in the aryl hydrocarbon receptor (AHR) gene with the risk of vitiligo in Han Chinese populations. Br J Dermatol 166(5):1081–1087

    PubMed  CAS  Google Scholar 

  57. Kitamura R, Tsukamoto K, Harada K, Shimizu A, Shimada S, Kobayashi T et al (2004) Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: role of SCF/KIT protein interactions and the downstream effector, MITF-M. J Pathol 202(4):463–475

    PubMed  CAS  Google Scholar 

  58. Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML, Pettersson S et al (2002) A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc Natl Acad Sci U S A 99(15):9990–9995

    PubMed  CAS  Google Scholar 

  59. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L et al (2004) A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64(14):4707–4710

    PubMed  CAS  Google Scholar 

  60. Haarmann-Stemmann T, Bothe H, Abel J (2009) Growth factors, cytokines, and their receptors as downstream targets of aryl hydrocarbon receptor (AhR) signaling pathways. Biochem Pharmacol 77(4):508–520

    PubMed  CAS  Google Scholar 

  61. Tauchi M, Hida A, Negishi T, Katsuoka F, Noda S, Mimura J et al (2005) Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. Mol Cell Biol 25(21):9360–9368

    PubMed  CAS  Google Scholar 

  62. Xue W, Warshawsky D (2005) Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol 206(1):73–93

    PubMed  CAS  Google Scholar 

  63. Godschalk R, Curfs D, Bartsch H, van Schooten FJ, Nair J (2003) Benzo[a]pyrene enhances lipid peroxidation induced DNA damage in aorta of apolipoprotein E knockout mice. Free Radic Res 37(12):1299–1305

    PubMed  CAS  Google Scholar 

  64. Diepgen TL, Mahler V (2002) The epidemiology of skin cancer. Br J Dermatol 146(Suppl 61):1–6

    PubMed  Google Scholar 

  65. Gelboin HV (1980) Benzo[alpha]pyrene metabolism, activation, and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol Rev 60(4):1107–1166

    PubMed  CAS  Google Scholar 

  66. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J et al (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 97(2):779–782

    PubMed  CAS  Google Scholar 

  67. Ide F, Suka N, Kitada M, Sakashita H, Kusama K, Ishikawa T (2004) Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor. Cancer Lett 214(1):35–41

    PubMed  CAS  Google Scholar 

  68. Hennings H, Devor D, Wenk ML, Slaga TJ, Former B, Colburn NH et al (1981) Comparison of two-stage epidermal carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene or N-methyl-N’-nitro-N-nitrosoguanidine in newborn and adult SENCAR and BALB/c mice. Cancer Res 41(3):773–779

    PubMed  CAS  Google Scholar 

  69. Balmain A, Ramsden M, Bowden GT, Smith J (1984) Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307(5952):658–660

    PubMed  CAS  Google Scholar 

  70. Buters J, Quintanilla-Martinez L, Schober W, Soballa VJ, Hintermair J, Wolff T et al (2003) CYP1B1 determines susceptibility to low doses of 7,12-dimethylbenz[a]anthracene-induced ovarian cancers in mice: correlation of CYP1B1-mediated DNA adducts with carcinogenicity. Carcinogenesis 24(2):327–334

    PubMed  CAS  Google Scholar 

  71. Savas U, Carstens CP, Jefcoate CR (1997) Biological oxidations and P450 reactions. Recombinant mouse CYP1B1 expressed in Escherichia coli exhibits selective binding by polycyclic hydrocarbons and metabolism which parallels C3H10T1/2 cell microsomes, but differs from human recombinant CYP1B1. Arch Biochem Biophys 347(2):181–192

    PubMed  CAS  Google Scholar 

  72. Wislocki PG, Gadek KM, Chou MW, Yang SK, Lu AY (1980) Carcinogenicity and mutagenicity of the 3,4-dihydrodiols and other metabolites of 7,12-dimethylbenz(a)anthracene and its hydroxymethyl derivatives. Cancer Res 40(10):3661–3664

    PubMed  CAS  Google Scholar 

  73. Tsuchiya Y, Nakajima M, Kyo S, Kanaya T, Inoue M, Yokoi T (2004) Human CYP1B1 is regulated by estradiol via estrogen receptor. Cancer Res 64(9):3119–3125

    PubMed  CAS  Google Scholar 

  74. Zheng W, Jefcoate CR (2005) Steroidogenic factor-1 interacts with cAMP response element-binding protein to mediate cAMP stimulation of CYP1B1 via a far upstream enhancer. Mol Pharmacol 67(2):499–512

    PubMed  CAS  Google Scholar 

  75. Uno S, Dalton TP, Shertzer HG, Genter MB, Warshawsky D, Talaska G et al (2001) Benzo[a]pyrene-induced toxicity: paradoxical protection in Cyp1a1(−/−) knockout mice having increased hepatic BaP-DNA adduct levels. Biochem Biophys Res Commun 289(5):1049–1056

    PubMed  CAS  Google Scholar 

  76. Haarmann-Stemmann T, Abel J, Fritsche E, Krutmann J (2012) The AhR-Nrf2 pathway in keratinocytes: on the road to chemoprevention? J Invest Dermatol 132(1):7–9

    PubMed  CAS  Google Scholar 

  77. Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85(4):241–272

    PubMed  CAS  Google Scholar 

  78. Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO et al (2006) Inhibition of 7,12-Dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res 66(16):8293–8296

    PubMed  CAS  Google Scholar 

  79. Rundhaug JE, Fischer SM (2008) Cyclo-oxygenase-2 plays a critical role in UV-induced skin carcinogenesis. Photochem Photobiol 84(2):322–329

    PubMed  CAS  Google Scholar 

  80. Ciolino HP, Daschner PJ, Yeh GC (1998) Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res 58(24):5707–5712

    PubMed  CAS  Google Scholar 

  81. Palermo CM, Hernando JI, Dertinger SD, Kende AS, Gasiewicz TA (2003) Identification of potential aryl hydrocarbon receptor antagonists in green tea. Chem Res Toxicol 16(7):865–872

    PubMed  CAS  Google Scholar 

  82. Aziz MH, Reagan-Shaw S, Wu J, Longley BJ, Ahmad N (2005) Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? FASEB J 19(9):1193–1195

    PubMed  CAS  Google Scholar 

  83. Lu YP, Lou YR, Xie JG, Peng QY, Liao J, Yang CS et al (2002) Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc Natl Acad Sci U S A 99(19):12455–12460

    PubMed  CAS  Google Scholar 

  84. Sun SY, Hail N Jr, Lotan R (2004) Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 96(9):662–672

    PubMed  CAS  Google Scholar 

  85. Rosette C, Karin M (1996) Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 274(5290):1194–1197

    PubMed  CAS  Google Scholar 

  86. Tran QT, Kennedy LH, Leon CS, Bodreddigari S, Goodwin SB, Sutter CH et al (2012) EGFR regulation of epidermal barrier function. Physiol Genomics 44(8):455–469

    PubMed  CAS  Google Scholar 

  87. Sutter CH, Yin H, Li Y, Mammen JS, Bodreddigari S, Stevens G et al (2009) EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes. Proc Natl Acad Sci U S A 106(11):4266–4271

    PubMed  Google Scholar 

  88. Takagi S, Tojo H, Tomita S, Sano S, Itami S, Hara M et al (2003) Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function. J Clin Invest 112(9):1372–1382

    PubMed  CAS  Google Scholar 

  89. Matsue H, Cruz PD Jr, Bergstresser PR, Takashima A (1992) Cytokine expression by epidermal cell subpopulations. J Invest Dermatol 99(5):42S–45S

    PubMed  CAS  Google Scholar 

  90. Williams IR, Kupper TS (1996) Immunity at the surface: homeostatic mechanisms of the skin immune system. Life Sci 58(18):1485–1507

    PubMed  CAS  Google Scholar 

  91. Lai ZW, Pineau T, Esser C (1996) Identification of dioxin-responsive elements (DREs) in the 5′ regions of putative dioxin-inducible genes. Chem Biol Interact 100(2):97–112

    PubMed  CAS  Google Scholar 

  92. Henley DV, Bellone CJ, Williams DA, Ruh MF (2004) MAPK signaling pathways modulate IL-1beta expression in human keratinocytes. Arch Biochem Biophys 424(1):112–118

    PubMed  CAS  Google Scholar 

  93. Tsuji G, Takahara M, Uchi H, Takeuchi S, Mitoma C, Moroi Y et al (2011) An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J Dermatol Sci 62(1):42–49

    PubMed  CAS  Google Scholar 

  94. Carvajal-Gonzalez JM, Roman AC, Cerezo-Guisado MI, Rico-Leo EM, Martin-Partido G, Fernandez-Salguero PM (2009) Loss of dioxin-receptor expression accelerates wound healing in vivo by a mechanism involving TGF{beta}. J Cell Sci 122(Pt 11):1823–1833

    PubMed  CAS  Google Scholar 

  95. Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, Romani N et al (2005) Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22(5):643–654

    PubMed  CAS  Google Scholar 

  96. Bennett CL, van Rijn E, Jung S, Inaba K, Steinman RM, Kapsenberg ML et al (2005) Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity. J Cell Biol 169(4):569–576

    PubMed  CAS  Google Scholar 

  97. Zhao X, Deak E, Soderberg K, Linehan M, Spezzano D, Zhu J et al (2003) Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2. J Exp Med 197(2):153–162

    PubMed  CAS  Google Scholar 

  98. Allan RS, Smith CM, Belz GT, van Lint AL, Wakim LM, Heath WR et al (2003) Epidermal viral immunity induced by CD8alpha + dendritic cells but not by Langerhans cells. Science 301(5641):1925–1928

    PubMed  CAS  Google Scholar 

  99. Puhvel SM, Sakamoto M, Reisner RM (1989) Effect of TCDD on the density of Langerhans cells in murine skin. Toxicol Appl Pharmacol 99(1):72–80

    PubMed  CAS  Google Scholar 

  100. Kadow S, Jux B, Zahner SP, Wingerath B, Chmill S, Clausen BE et al (2011) Aryl hydrocarbon receptor is critical for homeostasis of invariant gamma}{delta T cells in the murine epidermis. J Immunol 187(6):3104–3110

    PubMed  CAS  Google Scholar 

  101. Kadow S, Jux B, Chmill S, Esser C (2010) Small molecules as friends and foes of the immune system. Future Med Chem 1(9):1583–1591

    Google Scholar 

  102. Merk HF, Baron JM, Heise R, Fritsche E, Schroeder P, Abel J et al (2006) Concepts in molecular dermatotoxicology. Exp Dermatol 15(9):692–704

    PubMed  CAS  Google Scholar 

  103. Ito T, Inouye K, Nohara K, Tohyama C, Fujimaki H (2008) TCDD exposure exacerbates atopic dermatitis-related inflammation in NC/Nga mice. Toxicol Lett 177(1):31–37

    PubMed  CAS  Google Scholar 

  104. Vogel CF, Matsumura F (2009) A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol 77(4):734–745

    PubMed  CAS  Google Scholar 

  105. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K et al (2009) Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med 206(9):2027–2035

    PubMed  CAS  Google Scholar 

  106. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC et al (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109

    PubMed  CAS  Google Scholar 

  107. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E et al (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453(7191):65–71

    PubMed  CAS  Google Scholar 

  108. Ito M, Ogawa K, Takeuchi K, Nakada A, Heishi M, Suto H et al (2004) Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis. J Dermatol Sci 36(3):157–164

    PubMed  CAS  Google Scholar 

  109. Voorhis MV, Fechner JH, Zhang X, Mezrich JD (2012) The Aryl hydrocarbon receptor: a novel target for immunomodulation in organ transplantation. Transplantation

  110. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D et al (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11(9):854–861

    PubMed  CAS  Google Scholar 

  111. Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A et al (2010) Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 11(9):846–853

    PubMed  CAS  Google Scholar 

  112. Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA, Krueger JG (2009) Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production. Proc Natl Acad Sci U S A 106(51):21795–21800

    PubMed  CAS  Google Scholar 

  113. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10(8):864–871

    PubMed  CAS  Google Scholar 

  114. Zhang N, Pan HF, Ye DQ (2011) Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 353(1–2):41–46

    PubMed  CAS  Google Scholar 

  115. Wu HY, Quintana FJ, da Cunha AP, Dake BT, Koeglsperger T, Starossom SC et al (2011) In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PLoS One 6(8):e23618

    PubMed  CAS  Google Scholar 

  116. Girardi M, Lewis JM, Filler RB, Hayday AC, Tigelaar RE (2006) Environmentally responsive and reversible regulation of epidermal barrier function by gamma delta T cells. J Invest Dermatol 126(4):808–814

    PubMed  CAS  Google Scholar 

  117. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009) Interleukin-17-producing gamma delta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31(2):321–330

    PubMed  CAS  Google Scholar 

  118. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF et al (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. doi:10.1016/j.cell.2011.09.025

    Google Scholar 

  119. Ebert LM, Meuter S, Moser B (2006) Homing and function of human skin gamma delta T cells and NK cells: relevance for tumor surveillance. J Immunol 176(7):4331–4336

    PubMed  CAS  Google Scholar 

  120. Jameson J, Havran WL (2007) Skin gamma-delta T cell functions in homeostasis and wound healing. Immunol Rev 215:114–122

    PubMed  CAS  Google Scholar 

  121. Holtmeier W, Kabelitz D (2005) Gamma-delta T cells link innate and adaptive immune responses. Chem Immunol Allergy 86:151–183

    PubMed  CAS  Google Scholar 

  122. Laggner U, Di MP, Perera GK, Hundhausen C, Lacy KE, Ali N et al (2011) Identification of a novel proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a potential role in psoriasis. J Immunol 187(5):2783–2793

    PubMed  CAS  Google Scholar 

  123. Cai Y, Fleming C, Yan J (2012) New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol 9(4):302–309

    PubMed  CAS  Google Scholar 

  124. Prud’homme GJ (2012) Cancer stem cells and novel targets for antitumor strategies. Curr Pharm Des 18(19):2838–2849

    PubMed  Google Scholar 

  125. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S et al (2011) An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nat Geosci 478(7368):197–203

    CAS  Google Scholar 

  126. Ma Q (2011) Influence of light on aryl hydrocarbon receptor signaling and consequences in drug metabolism, physiology, and disease. Expert Opin Drug Metab Toxicol 7(10):1267–1293

    PubMed  CAS  Google Scholar 

  127. Korkina LG, Pastore S, Dellambra E, De LC (2012) New molecular and cellular targets for chemoprevention and treatment of skin tumors by plant polyphenols: a critical review. Curr Med Chem

  128. Platzer B, Richter S, Kneidinger D, Waltenberger D, Woisetschlager M, Strobl H (2009) Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J Immunol 183(1):66–74

    PubMed  CAS  Google Scholar 

  129. Sibilano R, Frossi B, Calvaruso M, Danelli L, Betto E, Dall’Agnese A et al (2012) The aryl hydrocarbon receptor modulates acute and late mast cell responses. J Immunol 189(1):120–127

    PubMed  CAS  Google Scholar 

  130. Cho YC, Zheng W, Jefcoate CR (2004) Disruption of cell–cell contact maximally but transiently activates AhR-mediated transcription in 10 T1/2 fibroblasts. Toxicol Appl Pharmacol 199(3):220–238

    PubMed  CAS  Google Scholar 

  131. Ju Q, Fimmel S, Hinz N, Stahlmann R, Xia L, Zouboulis CC (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro. Exp Dermatol 20(4):320–325

    PubMed  CAS  Google Scholar 

  132. Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA (2009) The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol 77(4):577–587

    PubMed  CAS  Google Scholar 

  133. Esser C, Rannug A, Stockinger B (2009) The aryl hydrocarbon receptor and immunity. Trends Immunol 9:447–454

    Google Scholar 

  134. Pauly SK, Fechner JH, Zhang X, Torrealba J, Bradfield CA, Mezrich JD (2012) The aryl hydrocarbon receptor influences transplant outcomes in response to environmental signals. Toxicol Environ Chem 94(6):1175–1187

    PubMed  CAS  Google Scholar 

  135. Schallreuter KU, Salem MA, Gibbons NC, Martinez A, Slominski R, Ludemann J et al (2012) Blunted epidermal l-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: epidermal H2O2/ONOO(−)-mediated stress abrogates tryptophan hydroxylase and Dopa decarboxylase activities, leading to low serotonin and melatonin levels. FASEB J 26(6):2457–2470

    PubMed  CAS  Google Scholar 

  136. Kramer HJ, Podobinska M, Bartsch A, Battmann A, Thoma W, Bernd A et al (2005) Malassezin, a novel agonist of the aryl hydrocarbon receptor from the yeast Malassezia furfur, induces apoptosis in primary human melanocytes. Chembiochem 6(5):860–865

    PubMed  Google Scholar 

  137. Gaitanis G, Magiatis P, Stathopoulou K, Bassukas ID, Alexopoulos EC, Velegraki A et al (2008) AhR ligands, malassezin, and indolo[3,2-b]carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis. J Invest Dermatol 128(7):1620–1625

    PubMed  CAS  Google Scholar 

  138. Gaido KW, Maness SC, Leonard LS, Greenlee WF (1992) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-dependent regulation of transforming growth factors-alpha and -beta 2 expression in a human keratinocyte cell line involves both transcriptional and post-transcriptional control. J Biol Chem 267(34):24591–24595

    PubMed  CAS  Google Scholar 

  139. Loertscher JA, Lin TM, Peterson RE, Allen-Hoffmann BL (2002) In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin causes accelerated terminal differentiation in fetal mouse skin. Toxicol Sci 68(2):465–472

    PubMed  CAS  Google Scholar 

  140. Sutter CH, Bodreddigari S, Campion C, Wible RS, Sutter TR (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation. Toxicol Sci 124(1):128–137

    PubMed  CAS  Google Scholar 

  141. Loertscher JA, Sattler CA, Allen-Hoffmann BL (2001) 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the differentiation pattern of human keratinocytes in organotypic culture. Toxicol Appl Pharmacol 175(2):121–129

    PubMed  CAS  Google Scholar 

  142. Villano CM, Murphy KA, Akintobi A, White LA (2006) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) expression and invasion in A2058 melanoma cells. Toxicol Appl Pharmacol 210(3):212–224

    PubMed  CAS  Google Scholar 

  143. Naldi L, Chatenoud L, Linder D, Belloni FA, Peserico A, Virgili AR et al (2005) Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case–control study. J Invest Dermatol 125(1):61–67

    PubMed  CAS  Google Scholar 

  144. D’Cruz D (2000) Autoimmune diseases associated with drugs, chemicals and environmental factors. Toxicol Lett 112–113:421–432

    PubMed  Google Scholar 

  145. Rieber N, Belohradsky BH (2010) AHR activation by tryptophan-pathogenic hallmark of Th17-mediated inflammation in eosinophilic fasciitis, eosinophilia-myalgia-syndrome, and toxic oil syndrome? Immunol Lett 128(2):154–155

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research of C.E. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG ES103/5-1 and 103/6-1). H.W. is supported by DFG WE2625/2-1 and the Leibnizgemeinschaft (SenatsausschussWettbewerb 2012). J.K. is supported by DFG FG871 and the ‘Bundesministerium für Bildung und Forschung Verbundprojekt UV’.

Author information

Authors and Affiliations

  1. Leibniz-Research Institute for Environmental Medicine (IUF), Auf’m Hennekamp 50, 40225, Dusseldorf, Germany

    Charlotte Esser, Imke Bargen, Heike Weighardt, Thomas Haarmann-Stemmann & Jean Krutmann

Authors
  1. Charlotte Esser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Imke Bargen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heike Weighardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Haarmann-Stemmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean Krutmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charlotte Esser.

Additional information

This article is a contribution to the special issue on Roles of Aryl Hydrocarbon Receptor in Controlling Immunity - Guest Editors: C. Pot, V. Kuchroo, and F. Quintaña

Rights and permissions

Reprints and permissions

About this article

Cite this article

Esser, C., Bargen, I., Weighardt, H. et al. Functions of the aryl hydrocarbon receptor in the skin. Semin Immunopathol 35, 677–691 (2013). https://doi.org/10.1007/s00281-013-0394-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-013-0394-4

Keywords

Search

Navigation