1932

Abstract

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-052220-115707
2022-01-06
2024-04-27
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/62/1/annurev-pharmtox-052220-115707.html?itemId=/content/journals/10.1146/annurev-pharmtox-052220-115707&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Cooper DY, Levin S, Narasimhulu S, Rosenthal O 1965. Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science 147:3656400–2
    [Google Scholar]
  2. 2. 
    Poland A, Glover E, Kende AS. 1976. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251:164936–46
    [Google Scholar]
  3. 3. 
    Bacsi SG, Hankinson O. 1996. Functional characterization of DNA-binding domains of the subunits of the heterodimeric aryl hydrocarbon receptor complex imputing novel and canonical basic helix-loop-helix protein-DNA interactions. J. Biol. Chem. 271:158843–50
    [Google Scholar]
  4. 4. 
    Denison MS, Nagy SR. 2003. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43:309–34
    [Google Scholar]
  5. 5. 
    Tête A, Gallais I, Imran M, Chevanne M, Liamin M et al. 2018. Mechanisms involved in the death of steatotic WIF-B9 hepatocytes co-exposed to benzo[a]pyrene and ethanol: a possible key role for xenobiotic metabolism and nitric oxide. Free Radic. Biol. Med. 129:323–37
    [Google Scholar]
  6. 6. 
    Ohtake F, Baba A, Takada I, Okada M, Iwasaki K et al. 2007. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446:7135562–66
    [Google Scholar]
  7. 7. 
    Jackson DP, Li H, Mitchell KA, Joshi AD, Elferink CJ. 2014. Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression. Mol. Pharmacol. 85:4533–41
    [Google Scholar]
  8. 8. 
    Tomkiewicz C, Herry L, Bui L-C, Métayer C, Bourdeloux M et al. 2013. The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway. Oncogene 32:141811–20
    [Google Scholar]
  9. 9. 
    Weber TJ, Ou X, Merchant M, Wang X, Safe SH, Ramos KS 1994. Biphasic modulation of protein kinase C (PKC) activity by polychlorinated dibenzo-p-dioxins (PCDDs) in serum-deprived rat aortic smooth muscle cells. J. Biochem. Toxicol. 9:3113–20
    [Google Scholar]
  10. 10. 
    Hanneman WH, Legare ME, Barhoumi R, Burghardt RC, Safe S, Tiffany-Castiglioni E. 1996. Stimulation of calcium uptake in cultured rat hippocampal neurons by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology 112:119–28
    [Google Scholar]
  11. 11. 
    Matsumura F. 2009. The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem. Pharmacol. 77:4608–26
    [Google Scholar]
  12. 12. 
    Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE. 2000. The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19:485498–506
    [Google Scholar]
  13. 13. 
    Tian Y, Ke S, Denison MS, Rabson AB, Gallo MA. 1999. Ah receptor and NF-κB interactions, a potential mechanism for dioxin toxicity. J. Biol. Chem. 274:1510–15
    [Google Scholar]
  14. 14. 
    Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y et al. 2003. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423:6939545–50
    [Google Scholar]
  15. 15. 
    Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M et al. 2003. The aryl hydrocarbon receptor mediates degradation of estrogen receptor α through activation of proteasomes. Mol. Cell. Biol. 23:61843–55
    [Google Scholar]
  16. 16. 
    Procházková J, Kabátková M, Bryja V, Umannová L, Bernatík O et al. 2011. The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors. Toxicol. Sci. 122:2349–60
    [Google Scholar]
  17. 17. 
    Xu G, Li Y, Yoshimoto K, Wu Q, Chen G et al. 2014. 2,3,7,8-Tetrachlorodibenzo-p-dioxin stimulates proliferation of HAPI microglia by affecting the Akt/GSK-3β/cyclin D1 signaling pathway. Toxicol. Lett. 224:3362–70
    [Google Scholar]
  18. 18. 
    Abbott BD, Birnbaum LS, Perdew GH. 1995. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev. Dyn. 204:2133–43
    [Google Scholar]
  19. 19. 
    Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA 1998. Expression of ARNT, ARNT2, HIF1α, HIF2α and Ah receptor mRNAs in the developing mouse. Mech. Dev. 73:1117–23
    [Google Scholar]
  20. 20. 
    Chevallier A, Mialot A, Petit J-M, Fernandez-Salguero P, Barouki R et al. 2013. Oculomotor deficits in aryl hydrocarbon receptor null mouse. PLOS ONE 8:1e53520
    [Google Scholar]
  21. 21. 
    Wakx A, Nedder M, Tomkiewicz-Raulet C, Dalmasso J, Chissey A et al. 2018. Expression, localization, and activity of the aryl hydrocarbon receptor in the human placenta. Int. J. Mol. Sci. 19:123762
    [Google Scholar]
  22. 22. 
    Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN et al. 1997. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2:10645–54
    [Google Scholar]
  23. 23. 
    Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS et al. 1995. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:5211722–26
    [Google Scholar]
  24. 24. 
    Abbott BD, Schmid JE, Brown JG, Wood CR, White RD et al. 1999. RT-PCR quantification of AHR, ARNT, GR, and CYP1A1 mRNA in craniofacial tissues of embryonic mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and hydrocortisone. Toxicol. Sci. 47:176–85
    [Google Scholar]
  25. 25. 
    Schmidt JV, Su GH, Reddy JK, Simon MC, Bradfield CA 1996. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. PNAS 93:136731–36
    [Google Scholar]
  26. 26. 
    Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C et al. 2000. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. PNAS 97:1910442–47
    [Google Scholar]
  27. 27. 
    Lahvis GP, Pyzalski RW, Glover E, Pitot HC, McElwee MK, Bradfield CA. 2005. The aryl hydrocarbon receptor is required for developmental closure of the ductus venosus in the neonatal mouse. Mol. Pharmacol. 67:3714–20
    [Google Scholar]
  28. 28. 
    McMillan BJ, Bradfield CA. 2007. The aryl hydrocarbon receptor sans xenobiotics: endogenous function in genetic model systems. Mol. Pharmacol. 72:3487–98
    [Google Scholar]
  29. 29. 
    Wang Q, Yang K, Han B, Sheng B, Yin J et al. 2018. Aryl hydrocarbon receptor inhibits inflammation in DSS‑induced colitis via the MK2/p‑MK2/TTP pathway. Int. J. Mol. Med. 41:2868–76
    [Google Scholar]
  30. 30. 
    Bravo-Ferrer I, Cuartero MI, Medina V, Ahedo-Quero D, Peña-Martínez C et al. 2019. Lack of the aryl hydrocarbon receptor accelerates aging in mice. FASEB J 33:1112644–54
    [Google Scholar]
  31. 31. 
    Mandal PK. 2005. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J. Comp. Physiol. B Biochem. Syst. Environ. Physiol. 175:4221–30
    [Google Scholar]
  32. 32. 
    Hahn ME. 2001. Dioxin toxicology and the aryl hydrocarbon receptor: insights from fish and other non-traditional models. Mar. Biotechnol. 3:Suppl. 1S224–38
    [Google Scholar]
  33. 33. 
    Hahn ME. 2002. Aryl hydrocarbon receptors: diversity and evolution. Chem. Biol. Interact. 141:1–2131–60
    [Google Scholar]
  34. 34. 
    Larigot L, Juricek L, Dairou J, Coumoul X. 2018. AhR signaling pathways and regulatory functions. Biochim. Open 7:1–9
    [Google Scholar]
  35. 35. 
    Brinkmann V, Ale-Agha N, Haendeler J, Ventura N 2019. The aryl hydrocarbon receptor (AhR) in the aging process: another puzzling role for this highly conserved transcription factor. Front. Physiol. 10:1561
    [Google Scholar]
  36. 36. 
    Brinkmann V, Schiavi A, Shaik A, Puchta DR, Ventura N. 2020. Dietary and environmental factors have opposite AhR-dependent effects on C. elegans healthspan. Aging 13:1104–33
    [Google Scholar]
  37. 37. 
    Denison MS, Rogers JM, Rushing SR, Jones CL, Tetangco SC, Heath-Pagliuso S. 2002. Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. Curr. Protoc. Toxicol. 11:4.8.1–45
    [Google Scholar]
  38. 38. 
    Ma Q, Whitlock JP 1996. The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Mol. Cell. Biol. 16:52144–50
    [Google Scholar]
  39. 39. 
    Weiss C, Kolluri SK, Kiefer F, Göttlicher M. 1996. Complementation of Ah receptor deficiency in hepatoma cells: negative feedback regulation and cell cycle control by the Ah receptor. Exp. Cell Res. 226:1154–63
    [Google Scholar]
  40. 40. 
    Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K et al. 1994. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J. Biol. Chem. 269:4427337–43
    [Google Scholar]
  41. 41. 
    McGuire J, Okamoto K, Whitelaw ML, Tanaka H, Poellinger L. 2001. Definition of a dioxin receptor mutant that is a constitutive activator of transcription: delineation of overlapping repression and ligand binding functions within the PAS domain. J. Biol. Chem. 276:4541841–49
    [Google Scholar]
  42. 42. 
    Hahn ME. 1998. The aryl hydrocarbon receptor: a comparative perspective. Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 121:1–323–53
    [Google Scholar]
  43. 43. 
    Ciolino HP, Daschner PJ, Yeh GC. 1999. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem. J. 340:3715–22
    [Google Scholar]
  44. 44. 
    Gouédard C, Barouki R, Morel Y. 2004. Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism. Mol. Cell. Biol. 24:125209–22
    [Google Scholar]
  45. 45. 
    Casper RF, Quesne M, Rogers IM, Shirota T, Jolivet A et al. 1999. Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol. Pharmacol. 56:4784–90
    [Google Scholar]
  46. 46. 
    Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. 1991. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. PNAS 88:219543–47
    [Google Scholar]
  47. 47. 
    Yin X-F, Chen J, Mao W, Wang Y-H, Chen M-H 2012. A selective aryl hydrocarbon receptor modulator 3,3′-Diindolylmethane inhibits gastric cancer cell growth. J. Exp. Clin. Cancer Res. 31:46
    [Google Scholar]
  48. 48. 
    Vang O, Jensen H, Autrup H. 1991. Induction of cytochrome P-450IA1, IA2, IIB1, IIB2 and IIE1 by broccoli in rat liver and colon. Chem. Biol. Interact. 78:185–96
    [Google Scholar]
  49. 49. 
    Kall MA, Vang O, Clausen J. 1996. Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis 17:4793–99
    [Google Scholar]
  50. 50. 
    Miller CA. 1997. Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds. J. Biol. Chem. 272:5232824–29
    [Google Scholar]
  51. 51. 
    Heath-Pagliuso S, Rogers WJ, Tullis K, Seidel SD, Cenijn PH et al. 1998. Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 37:3311508–15
    [Google Scholar]
  52. 52. 
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I et al. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:7368197–203
    [Google Scholar]
  53. 53. 
    Rannug A, Rannug U, Rosenkranz HS, Winqvist L, Westerholm R 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. 262:3215422–27
    [Google Scholar]
  54. 54. 
    Collins SL, Patterson AD. 2020. The gut microbiome: an orchestrator of xenobiotic metabolism. Acta Pharm. Sin. B 10:119–32
    [Google Scholar]
  55. 55. 
    Jin U-H, Lee S-O, Sridharan G, Lee K, Davidson LA et al. 2014. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol. 85:5777–88
    [Google Scholar]
  56. 56. 
    Moura-Alves P, Faé K, Houthuys E, Dorhoi A, Kreuchwig A et al. 2014. AhR sensing of bacterial pigments regulates antibacterial defence. Nature 512:7515387–92
    [Google Scholar]
  57. 57. 
    Wu D, Li W, Lok P, Matsumura F, Vogel CFA 2011. AhR deficiency impairs expression of LPS-induced inflammatory genes in mice. Biochem. Biophys. Res. Commun. 410:2358–63
    [Google Scholar]
  58. 58. 
    Adachi J, Mori Y, Matsui S, Takigami H, Fujino J et al. 2001. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J. Biol. Chem. 276:3431475–78
    [Google Scholar]
  59. 59. 
    Guengerich FP, Martin MV, McCormick WA, Nguyen LP, Glover E, Bradfield CA. 2004. Aryl hydrocarbon receptor response to indigoids in vitro and in vivo. Arch. Biochem. Biophys. 423:2309–16
    [Google Scholar]
  60. 60. 
    Phelan D, Winter GM, Rogers WJ, Lam JC, Denison MS. 1998. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch. Biochem. Biophys. 357:1155–63
    [Google Scholar]
  61. 61. 
    Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD et al. 2011. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13:2144–51
    [Google Scholar]
  62. 62. 
    Esser C, Rannug A. 2015. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol. Rev. 67:2259–79
    [Google Scholar]
  63. 63. 
    Han H, Davidson LA, Hensel M, Yoon G, Landrock K et al. 2021. Loss of aryl hydrocarbon receptor promotes colon tumorigenesis in ApcS580/+; KrasG12D/+ mice. Mol. Cancer Res. 19:5771–83
    [Google Scholar]
  64. 64. 
    Rannug A. 2020. How the AHR became important in intestinal homeostasis—a diurnal FICZ/AHR/CYP1A1 feedback controls both immunity and immunopathology. Int. J. Mol. Sci. 21:165681
    [Google Scholar]
  65. 65. 
    Marinelli L, Martin-Gallausiaux C, Bourhis J-M, Béguet-Crespel F, Blottière HM, Lapaque N. 2019. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci. Rep. 9:1643
    [Google Scholar]
  66. 66. 
    Lamas B, Hernandez-Galan L, Galipeau HJ, Constante M, Clarizio A et al. 2020. Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation. Sci. Transl. Med. 12:566eaba0624
    [Google Scholar]
  67. 67. 
    Lamas B, Natividad JM, Sokol H 2018. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol 11:41024–38
    [Google Scholar]
  68. 68. 
    Guerrina N, Traboulsi H, Rico de Souza A, Bossé Y, Thatcher TH et al. 2021. Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms. FASEB J 35:3e21376
    [Google Scholar]
  69. 69. 
    Tsay JJ, Tchou-Wong K-M, Greenberg AK, Pass H, Rom WN. 2013. Aryl hydrocarbon receptor and lung cancer. Anticancer Res 33:41247–56
    [Google Scholar]
  70. 70. 
    Rothhammer V, Quintana FJ. 2019. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19:3184–97
    [Google Scholar]
  71. 71. 
    Head JL, Lawrence BP. 2009. The aryl hydrocarbon receptor is a modulator of anti-viral immunity. Biochem. Pharmacol. 77:4642–53
    [Google Scholar]
  72. 72. 
    Chen J-Y, Li C-F, Kuo C-C, Tsai KK, Hou M-F, Hung W-C. 2014. Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Res 16:4410
    [Google Scholar]
  73. 73. 
    Vogel CFA, Li W, Wu D, Miller JK, Sweeney C et al. 2011. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch. Biochem. Biophys. 512:178–86
    [Google Scholar]
  74. 74. 
    Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L et al. 2008. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:7191106–9
    [Google Scholar]
  75. 75. 
    Stobbe-Maicherski N, Wolff S, Wolff C, Abel J, Sydlik U et al. 2013. The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells. FEBS J 280:246681–90
    [Google Scholar]
  76. 76. 
    Guarnieri T. 2020. Aryl hydrocarbon receptor connects inflammation to breast cancer. Int. J. Mol. Sci. 21:155264
    [Google Scholar]
  77. 77. 
    Kado S, Chang WLW, Chi AN, Wolny M, Shepherd DM, Vogel CFA. 2017. Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells. Arch. Toxicol. 91:52209–21
    [Google Scholar]
  78. 78. 
    Benson JM, Shepherd DM. 2011. Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells. Toxicol. Sci. 124:2327–38
    [Google Scholar]
  79. 79. 
    Wakamatsu T, Yamamoto S, Ito T, Sato Y, Matsuo K et al. 2018. Indoxyl sulfate promotes macrophage IL-1β production by activating aryl hydrocarbon receptor/NF-κ/MAPK cascades, but the NLRP3 inflammasome was not activated. Toxins 10:3124
    [Google Scholar]
  80. 80. 
    Hubbard TD, Murray IA, Perdew GH 2015. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab. Dispos. 43:101522–35
    [Google Scholar]
  81. 81. 
    Der Vartanian A, Quétin M, Michineau S, Auradé F, Hayashi S et al. 2019. PAX3 confers functional heterogeneity in skeletal muscle stem cell responses to environmental stress. Cell Stem Cell 24:6958–73.e9
    [Google Scholar]
  82. 82. 
    Zalc A, Rattenbach R, Auradé F, Cadot B, Relaix F 2015. Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects. Dev. Cell 33:156–66
    [Google Scholar]
  83. 83. 
    Wang Q, Kurita H, Carreira V, Ko C-I, Fan Y et al. 2016. Ah receptor activation by dioxin disrupts activin, BMP, and WNT signals during the early differentiation of mouse embryonic stem cells and inhibits cardiomyocyte functions. Toxicol. Sci. 149:2346–57
    [Google Scholar]
  84. 84. 
    Kurita H, Carreira VS, Fan Y, Jiang M, Naticchioni M et al. 2016. Ah receptor expression in cardiomyocytes protects adult female mice from heart dysfunction induced by TCDD exposure. Toxicology355–3569–20
    [Google Scholar]
  85. 85. 
    Sauzeau V, Carvajal-González JM, Riolobos AS, Sevilla MA, Menacho-Márquez M et al. 2011. Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene. J. Biol. Chem. 286:42896–909
    [Google Scholar]
  86. 86. 
    Bock KW. 2019. Human AHR functions in vascular tissue: pro- and anti-inflammatory responses of AHR agonists in atherosclerosis. Biochem. Pharmacol. 159:116–20
    [Google Scholar]
  87. 87. 
    Vogel CFA, Sciullo E, Matsumura F 2004. Activation of inflammatory mediators and potential role of ah-receptor ligands in foam cell formation. Cardiovasc. Toxicol. 4:4363–73
    [Google Scholar]
  88. 88. 
    Vogel CFA, Nishimura N, Sciullo E, Wong P, Li W, Matsumura F 2007. Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch. Biochem. Biophys. 461:2169–75
    [Google Scholar]
  89. 89. 
    Yisireyili M, Saito S, Abudureyimu S, Adelibieke Y, Ng H-Y et al. 2014. Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells. PLOS ONE 9:10e109268
    [Google Scholar]
  90. 90. 
    Hennig B, Meerarani P, Slim R, Toborek M, Daugherty A et al. 2002. Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. Toxicol. Appl. Pharmacol. 181:3174–83
    [Google Scholar]
  91. 91. 
    Zhao H, Chen L, Yang T, Feng Y-L, Vaziri ND et al. 2019. Aryl hydrocarbon receptor activation mediates kidney disease and renal cell carcinoma. J. Transl. Med. 17:1302
    [Google Scholar]
  92. 92. 
    Schroeder JC, Dinatale BC, Murray IA, Flaveny CA, Liu Q et al. 2010. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49:2393–400
    [Google Scholar]
  93. 93. 
    Sallée M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S. 2014. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins 6:3934–49
    [Google Scholar]
  94. 94. 
    Brito JS, Borges NA, Esgalhado M, Magliano DC, Soulage CO, Mafra D. 2017. Aryl hydrocarbon receptor activation in chronic kidney disease: role of uremic toxins. Nephron 137:11–7
    [Google Scholar]
  95. 95. 
    Ichii O, Otsuka-Kanazawa S, Nakamura T, Ueno M, Kon Y et al. 2014. Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLOS ONE 9:9e108448
    [Google Scholar]
  96. 96. 
    Hamano H, Ikeda Y, Watanabe H, Horinouchi Y, Izawa-Ishizawa Y et al. 2018. The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease. Nephrol. Dial. Transplant. 33:4586–97
    [Google Scholar]
  97. 97. 
    Watanabe I, Tatebe J, Namba S, Koizumi M, Yamazaki J, Morita T 2013. Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. Circ. J. 77:1224–30
    [Google Scholar]
  98. 98. 
    Dou L, Sallée M, Cerini C, Poitevin S, Gondouin B et al. 2015. The cardiovascular effect of the uremic solute indole-3 acetic acid. J. Am. Soc. Nephrol. 26:4876–87
    [Google Scholar]
  99. 99. 
    Dou L, Poitevin S, Sallée M, Addi T, Gondouin B et al. 2018. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int 93:4986–99
    [Google Scholar]
  100. 100. 
    Shivanna S, Kolandaivelu K, Shashar M, Belghasim M, Al-Rabadi L et al. 2016. The aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in uremia. J. Am. Soc. Nephrol. 27:1189–201
    [Google Scholar]
  101. 101. 
    Kim HY, Yoo T-H, Hwang Y, Lee GH, Kim B et al. 2017. Indoxyl sulfate (IS)-mediated immune dysfunction provokes endothelial damage in patients with end-stage renal disease (ESRD). Sci. Rep. 7:13057
    [Google Scholar]
  102. 102. 
    Kim JT, Kim SS, Jun DW, Hwang YH, Park W-H et al. 2013. Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy. J. Diabetes Investig. 4:5483–91
    [Google Scholar]
  103. 103. 
    Ng H-Y, Yisireyili M, Saito S, Lee C-T, Adelibieke Y et al. 2014. Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. PLOS ONE 9:3e91517
    [Google Scholar]
  104. 104. 
    Ishida M, Mikami S, Kikuchi E, Kosaka T, Miyajima A et al. 2010. Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer. Carcinogenesis 31:2287–95
    [Google Scholar]
  105. 105. 
    Harrill JA, Hukkanen RR, Lawson M, Martin G, Gilger B et al. 2013. Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice. Toxicol. Appl. Pharmacol. 272:2503–18
    [Google Scholar]
  106. 106. 
    Juricek L, Carcaud J, Pelhaitre A, Riday TT, Chevallier A et al. 2017. AhR-deficiency as a cause of demyelinating disease and inflammation. Sci. Rep. 7:19794
    [Google Scholar]
  107. 107. 
    Mayer AK, Mahajnah M, Thomas MG, Cohen Y, Habib A et al. 2019. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain 142:61528–34
    [Google Scholar]
  108. 108. 
    Borovok N, Weiss C, Sharkia R, Reichenstein M, Wissinger B et al. 2020. Gene and protein expression in subjects with a nystagmus-associated AHR mutation. Front. Genet. 11:582796
    [Google Scholar]
  109. 109. 
    Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D et al. 2018. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. PNAS 115:6E1319–28
    [Google Scholar]
  110. 110. 
    de la Parra J, Cuartero MI, Pérez-Ruiz A, García-Culebras A, Martín R et al. 2018. AhR deletion promotes aberrant morphogenesis and synaptic activity of adult-generated granule neurons and impairs hippocampus-dependent memory. eNeuro 5:4ENEURO.0370-17.2018
    [Google Scholar]
  111. 111. 
    Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C et al. 2008. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J. Neurochem. 107:61518–28
    [Google Scholar]
  112. 112. 
    Beamer CA, Kreitinger JM, Cole SL, Shepherd DM 2019. Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin. Arch. Toxicol. 93:2355–68
    [Google Scholar]
  113. 113. 
    Strassel C, Brouard N, Mallo L, Receveur N, Mangin P et al. 2016. Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets. Blood 127:182231–40
    [Google Scholar]
  114. 114. 
    Murray IA, Patterson AD, Perdew GH. 2014. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer 14:12801–14
    [Google Scholar]
  115. 115. 
    Zudaire E, Cuesta N, Murty V, Woodson K, Adams L et al. 2008. The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J. Clin. Investig. 118:2640–50
    [Google Scholar]
  116. 116. 
    DiNatale BC, Schroeder JC, Perdew GH. 2011. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol. Carcinog. 50:3173–83
    [Google Scholar]
  117. 117. 
    DiNatale BC, Schroeder JC, Francey LJ, Kusnadi A, Perdew GH 2010. Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling. J. Biol. Chem. 285:3224388–97
    [Google Scholar]
  118. 118. 
    Stanford EA, Wang Z, Novikov O, Mulas F, Landesman-Bollag E et al. 2016. The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. BMC Biol 14:20
    [Google Scholar]
  119. 119. 
    Hayashibara T, Yamada Y, Mori N, Harasawa H, Sugahara K et al. 2003. Possible involvement of aryl hydrocarbon receptor (AhR) in adult T-cell leukemia (ATL) leukemogenesis: constitutive activation of AhR in ATL. Biochem. Biophys. Res. Commun. 300:1128–34
    [Google Scholar]
  120. 120. 
    Liu Z, Wu X, Zhang F, Han L, Bao G et al. 2013. AhR expression is increased in hepatocellular carcinoma. J. Mol. Histol. 44:4455–61
    [Google Scholar]
  121. 121. 
    Li Z-D, Wang K, Yang X-W, Zhuang Z-G, Wang J-J, Tong X-W. 2014. Expression of aryl hydrocarbon receptor in relation to p53 status and clinicopathological parameters in breast cancer. Int. J. Clin. Exp. Pathol. 7:117931–37
    [Google Scholar]
  122. 122. 
    Stanford EA, Ramirez-Cardenas A, Wang Z, Novikov O, Alamoud K et al. 2016. Role for the aryl hydrocarbon receptor and diverse ligands in oral squamous cell carcinoma migration and tumorigenesis. Mol. Cancer Res. 14:8696–706
    [Google Scholar]
  123. 123. 
    Brooks J, Eltom SE. 2011. Malignant transformation of mammary epithelial cells by ectopic overexpression of the aryl hydrocarbon receptor. Curr. Cancer Drug Targets 11:5654–69
    [Google Scholar]
  124. 124. 
    Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML et al. 2002. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. PNAS 99:159990–95
    [Google Scholar]
  125. 125. 
    Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C et al. 2004. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64:144707–10
    [Google Scholar]
  126. 126. 
    Currier N, Solomon SE, Demicco EG, Chang DLF, Farago M et al. 2005. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol. Pathol. 33:6726–37
    [Google Scholar]
  127. 127. 
    Trombino AF, Near RI, Matulka RA, Yang S, Hafer LJ et al. 2000. Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis. Breast Cancer Res. Treat. 63:2117–31
    [Google Scholar]
  128. 128. 
    Koliopanos A, Kleeff J, Xiao Y, Safe S, Zimmermann A et al. 2002. Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer. Oncogene 21:396059–70
    [Google Scholar]
  129. 129. 
    Chang JT, Chang H, Chen P-H, Lin S-L, Lin P 2007. Requirement of aryl hydrocarbon receptor overexpression for CYP1B1 up-regulation and cell growth in human lung adenocarcinomas. Clin. Cancer Res. 13:138–45
    [Google Scholar]
  130. 130. 
    Ishida M, Mikami S, Shinojima T, Kosaka T, Mizuno R et al. 2015. Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. Int. J. Cancer 137:2299–310
    [Google Scholar]
  131. 131. 
    Zhao S, Ohara S, Kanno Y, Midorikawa Y, Nakayama M et al. 2013. HER2 overexpression-mediated inflammatory signaling enhances mammosphere formation through up-regulation of aryl hydrocarbon receptor transcription. Cancer Lett 330:141–48
    [Google Scholar]
  132. 132. 
    Yamashita N, Saito N, Zhao S, Terai K, Hiruta N et al. 2018. Heregulin-induced cell migration is promoted by aryl hydrocarbon receptor in HER2-overexpressing breast cancer cells. Exp. Cell Res. 366:134–40
    [Google Scholar]
  133. 133. 
    Goode GD, Ballard BR, Manning HC, Freeman ML, Kang Y, Eltom SE. 2013. Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB-231 human breast cancer cell line. Int. J. Cancer 133:122769–80
    [Google Scholar]
  134. 134. 
    Diry M, Tomkiewicz C, Koehle C, Coumoul X, Bock KW et al. 2006. Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism. Oncogene 25:405570–74
    [Google Scholar]
  135. 135. 
    John K, Lahoti TS, Wagner K, Hughes JM, Perdew GH. 2014. The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. Mol. Carcinog. 53:10765–76
    [Google Scholar]
  136. 136. 
    Kanno Y, Takane Y, Izawa T, Nakahama T, Inouye Y 2006. The inhibitory effect of aryl hydrocarbon receptor repressor (AhRR) on the growth of human breast cancer MCF-7 cells. Biol. Pharm. Bull. 29:61254–57
    [Google Scholar]
  137. 137. 
    Belguise K, Guo S, Yang S, Rogers AE, Seldin DC et al. 2007. Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. Cancer Res 67:2411742–50
    [Google Scholar]
  138. 138. 
    Schiering C, Vonk A, Das S, Stockinger B, Wincent E. 2018. Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem. Pharmacol. 151:47–58
    [Google Scholar]
  139. 139. 
    Mulero-Navarro S, Pozo-Guisado E, Pérez-Mancera PA, Alvarez-Barrientos A, Catalina-Fernández I et al. 2005. Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model. J. Biol. Chem. 280:3128731–41
    [Google Scholar]
  140. 140. 
    Goode G, Pratap S, Eltom SE 2014. Depletion of the aryl hydrocarbon receptor in MDA-MB-231 human breast cancer cells altered the expression of genes in key regulatory pathways of cancer. PLOS ONE 9:6e100103
    [Google Scholar]
  141. 141. 
    Jeffy BD, Chirnomas RB, Romagnolo DF. 2002. Epigenetics of breast cancer: polycyclic aromatic hydrocarbons as risk factors. Environ. Mol. Mutagen. 39:2–3235–44
    [Google Scholar]
  142. 142. 
    Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A et al. 2016. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER-/PR-/Her2- human breast cancer cells. Mol. Pharmacol. 90:5674–88
    [Google Scholar]
  143. 143. 
    DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS et al. 2010. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci. 115:189–97
    [Google Scholar]
  144. 144. 
    Litzenburger UM, Opitz CA, Sahm F, Rauschenbach KJ, Trump S et al. 2014. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget 5:41038–51
    [Google Scholar]
  145. 145. 
    Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS. 2010. Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. Mol. Endocrinol. 24:2359–69
    [Google Scholar]
  146. 146. 
    Gramatzki D, Pantazis G, Schittenhelm J, Tabatabai G, Köhle C et al. 2009. Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells. Oncogene 28:282593–605
    [Google Scholar]
  147. 147. 
    Korzeniewski N, Wheeler S, Chatterjee P, Duensing A, Duensing S. 2010. A novel role of the aryl hydrocarbon receptor (AhR) in centrosome amplification—implications for chemoprevention. Mol. Cancer 9:153
    [Google Scholar]
  148. 148. 
    Zhao S, Kanno Y, Nakayama M, Makimura M, Ohara S, Inouye Y. 2012. Activation of the aryl hydrocarbon receptor represses mammosphere formation in MCF-7 cells. Cancer Lett 317:2192–98
    [Google Scholar]
  149. 149. 
    Zhang S, Kim K, Jin UH, Pfent C, Cao H et al. 2012. Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol. Cancer Ther. 11:1108–18
    [Google Scholar]
  150. 150. 
    Jin U-H, Lee S-O, Pfent C, Safe S 2014. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer 14:498
    [Google Scholar]
  151. 151. 
    Prud'homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S 2010. Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLOS ONE 5:11e13831
    [Google Scholar]
  152. 152. 
    Chakrabarti R, Subramaniam V, Abdalla S, Jothy S, Prud'homme GJ 2009. Tranilast inhibits the growth and metastasis of mammary carcinoma. Anticancer Drugs 20:5334–45
    [Google Scholar]
  153. 153. 
    Subramaniam V, Ace O, Prud'homme GJ, Jothy S 2011. Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells. Exp. Mol. Pathol. 90:1116–22
    [Google Scholar]
  154. 154. 
    Zhang S, Lei P, Liu X, Li X, Walker K et al. 2009. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr. Relat. Cancer 16:3835–44
    [Google Scholar]
  155. 155. 
    Jin U-H, Kim S-B, Safe S 2015. Omeprazole inhibits pancreatic cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem. Res. Toxicol. 28:5907–18
    [Google Scholar]
  156. 156. 
    Fan Y, Boivin GP, Knudsen ES, Nebert DW, Xia Y, Puga A. 2010. The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res 70:1212–20
    [Google Scholar]
  157. 157. 
    Wang W, Smith R, Safe S 1998. Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes. Arch. Biochem. Biophys. 356:2239–48
    [Google Scholar]
  158. 158. 
    McDougal A, Wormke M, Calvin J, Safe S 2001. Tamoxifen-induced antitumorigenic/antiestrogenic action synergized by a selective aryl hydrocarbon receptor modulator. Cancer Res 61:103902–7
    [Google Scholar]
  159. 159. 
    Fritz WA, Lin T-M, Cardiff RD, Peterson RE. 2007. The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice. Carcinogenesis 28:2497–505
    [Google Scholar]
  160. 160. 
    Safe S, Lee S-O, Jin U-H. 2013. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci. 135:11–16
    [Google Scholar]
  161. 161. 
    Rothhammer V, Borucki DM, Kenison JE, Hewson P, Wang Z et al. 2018. Detection of aryl hydrocarbon receptor agonists in human samples. Sci. Rep. 8:14970
    [Google Scholar]
  162. 162. 
    Lin P, Chang H, Tsai W-T, Wu M-H, Liao Y-S et al. 2003. Overexpression of aryl hydrocarbon receptor in human lung carcinomas. Toxicol. Pathol. 31:122–30
    [Google Scholar]
  163. 163. 
    Larsen MC, Brake PB, Pollenz RS, Jefcoate CR. 2004. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis. Toxicol. Sci. 82:146–61
    [Google Scholar]
  164. 164. 
    Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE et al. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46:2279–303
    [Google Scholar]
  165. 165. 
    Barhoover MA, Hall JM, Greenlee WF, Thomas RS. 2010. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol. Pharmacol. 77:2195–201
    [Google Scholar]
  166. 166. 
    Wang K, Li Y, Jiang Y-Z, Dai C-F, Patankar MS et al. 2013. An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells. Cancer Lett 340:163–71
    [Google Scholar]
  167. 167. 
    Corre S, Tardif N, Mouchet N, Leclair HM, Boussemart L et al. 2018. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 9:14775
    [Google Scholar]
  168. 168. 
    Narasimhan S, Stanford Zulick E, Novikov O, Parks AJ, Schlezinger JJ et al. 2018. Towards resolving the pro- and anti-tumor effects of the aryl hydrocarbon receptor. Int. J. Mol. Sci. 19:51388
    [Google Scholar]
  169. 169. 
    Safe S, Cheng Y, Jin U-H. 2017. The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy. Curr. Opin. Toxicol. 2:24–29
    [Google Scholar]
  170. 170. 
    Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C et al. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ. Health Perspect. 125:3428–36
    [Google Scholar]
  171. 171. 
    Pierre S, Chevallier A, Teixeira-Clerc F, Ambolet-Camoit A, Bui L-C et al. 2014. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol. Sci. 137:1114–24
    [Google Scholar]
  172. 172. 
    Joffin N, Noirez P, Antignac J-P, Kim M-J, Marchand P et al. 2018. Release and toxicity of adipose tissue-stored TCDD: direct evidence from a xenografted fat model. Environ. Int. 121:Pt. 21113–20
    [Google Scholar]
  173. 173. 
    Rojas IY, Moyer BJ, Ringelberg CS, Wilkins OM, Pooler DB et al. 2021. Kynurenine-induced aryl hydrocarbon receptor signaling in mice causes body mass gain, liver steatosis, and hyperglycemia. Obesity 29:2337–49
    [Google Scholar]
  174. 174. 
    Haarmann-Stemmann T, Sutter TR, Krutmann J, Esser C 2021. The mode of action of tapinarof may not solely depend on the activation of cutaneous AHR signaling but also on its antimicrobial activity. J. Am. Acad. Dermatol. 85:E33–34
    [Google Scholar]
  175. 175. 
    Robbins K, Bissonnette R, Maeda-Chubachi T, Ye L, Peppers J et al. 2019. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis. J. Am. Acad. Dermatol. 80:3714–21
    [Google Scholar]
  176. 176. 
    Yuan X, Dou Y, Wu X, Wei Z, Dai Y 2017. Tetrandrine, an agonist of aryl hydrocarbon receptor, reciprocally modulates the activities of STAT3 and STAT5 to suppress Th17 cell differentiation. J. Cell Mol. Med. 21:92172–83
    [Google Scholar]
  177. 177. 
    Tong B, Yuan X, Dou Y, Wu X, Chou G et al. 2016. Norisoboldine, an isoquinoline alkaloid, acts as an aryl hydrocarbon receptor ligand to induce intestinal Treg cells and thereby attenuate arthritis. Int. J. Biochem. Cell Biol. 75:63–73
    [Google Scholar]
  178. 178. 
    Dinesh P, Rasool M. 2019. Berberine mitigates IL-21/IL-21R mediated autophagic influx in fibroblast-like synoviocytes and regulates Th17/Treg imbalance in rheumatoid arthritis. Apoptosis 24:7–8644–61
    [Google Scholar]
  179. 179. 
    Tong B, Yuan X, Dou Y, Wu X, Wang Y et al. 2016. Sinomenine induces the generation of intestinal Treg cells and attenuates arthritis via activation of aryl hydrocarbon receptor. Lab. Investig. 96:101076–86
    [Google Scholar]
  180. 180. 
    Chen I, Hsieh T, Thomas T, Safe S 2001. Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene 262:1–2207–14
    [Google Scholar]
  181. 181. 
    Khan AS, Langmann T. 2020. Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration. J. Neuroinflamm. 17:1327
    [Google Scholar]
  182. 182. 
    Megna BW, Carney PR, Depke MG, Nukaya M, McNally J et al. 2017. The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer. J. Surg. Res. 213:16–24
    [Google Scholar]
  183. 183. 
    Smits JPH, Ederveen THA, Rikken G, van den Brink NJM, van Vlijmen-Willems IMJJ et al. 2020. Targeting the cutaneous microbiota in atopic dermatitis by coal tar via AHR-dependent induction of antimicrobial peptides. J. Investig. Dermatol. 140:2415–24.e10
    [Google Scholar]
  184. 184. 
    Lv Q, Wang K, Qiao S, Yang L, Xin Y et al. 2018. Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway. Cell Death Dis 9:3258
    [Google Scholar]
  185. 185. 
    Mohammadi S, Memarian A, Sedighi S, Behnampour N, Yazdani Y. 2018. Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: a crucial role for aryl hydrocarbon receptor. Autoimmunity 51:5199–209
    [Google Scholar]
  186. 186. 
    Lieberman I, Lentz DP, Trucco GA, Seow WK, Thong YH. 1992. Prevention by tetrandrine of spontaneous development of diabetes mellitus in BB rats. Diabetes 41:5616–19
    [Google Scholar]
  187. 187. 
    Gu B, Zeng Y, Yin C, Wang H, Yang X et al. 2012. Sinomenine reduces iNOS expression via inhibiting the T-bet IFN-γ pathway in experimental autoimmune encephalomyelitis in rats. J. Biomed. Res. 26:6448–55
    [Google Scholar]
  188. 188. 
    Giovannoni F, Li Z, Garcia CC, Quintana FJ 2020. A potential role for AHR in SARS-CoV-2 pathology. Res. Sq. https://doi.org/10.21203/rs.3.rs-25639/v1
    [Crossref] [Google Scholar]
  189. 189. 
    Giovannoni F, Bosch I, Polonio CM, Torti MF, Wheeler MA et al. 2020. AHR is a Zika virus host factor and a candidate target for antiviral therapy. Nat. Neurosci. 23:8939–51
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-052220-115707
Loading
/content/journals/10.1146/annurev-pharmtox-052220-115707
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error