Cellular and Molecular Life Sciences

, Volume 73, Issue 1, pp 95–117 | Cite as

The emerging role of aryl hydrocarbon receptor in the activation and differentiation of Th17 cells

  • Eszter Baricza
  • Viola Tamási
  • Nikolett Marton
  • Edit I. Buzás
  • György NagyEmail author


The aryl hydrocarbon receptor (AHR) is a cytoplasmic transcription factor, which plays an essential role in the xenobiotic metabolism in a wide variety of cells. The AHR gene is evolutionarily conserved and it has a central role not only in the differentiation and maturation of many tissues, but also in the toxicological metabolism of the cell by the activation of metabolizing enzymes. Several lines of evidence support that both AHR agonists and antagonists have profound immunological effects; and recently, the AHR has been implicated in antibacterial host defense. According to recent studies, the AHR is essential for the differentiation and activation of T helper 17 (Th17) cells. It is well known that Th17 cells have a central role in the development of inflammation, which is crucial in the defense against pathogens. In addition, Th17 cells play a major role in the pathogenesis of several autoimmune diseases such as rheumatoid arthritis. Therefore, the AHR may provide connection between the environmental chemicals, the immune regulation, and autoimmunity. In the present review, we summarize the role of the AHR in the Th17 cell functions.


Aryl hydrocarbon receptor Th17 cell Polycyclic aromatic hydrocarbons RAR-related orphan nuclear receptor gamma t 







Aryl hydrocarbon receptor


Nuclear AHR repressor


Androgen receptor


Aryl hydrocarbon receptor nuclear translocator




Blood–brain barrier endothelial cells


Bechet’s disease


Basic helix–loop–helix/Per–Arnt–Sim


CREB-binding protein/E1A binding protein p300 protein


Chemokine (C–C motif) ligand 20


Chemokine receptor 6


2-Methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide


V-Maf avian musculoaponeuroticfibrosarcoma oncogene homolog


Central nervous system


Chemokine (C-X-C motif) ligand 1


Cytochrome P450, family 1, subfamily A, polypeptide 1


Dendritic cells






Experimental autoimmune encephalomyelitis


Endothelial NO synthase


Estrogen receptor


Estrogen response element


Estrogen receptor alpha




Forkhead box P3




Granulocyte colony-stimulating factor


Granulocyte–monocyte colony-stimulating factor


Halogenated-dioxins and their congeners


Heat shock protein 90




Indoxyl 3-sulfate


Inflammatory bowel disease


2,3-Dioxygenase 1


2,3-Dioxygenase 2


Interferon gamma


Innate lymphoid cell


Isolated lymphoid follicles


Intraepithelial lymphocytes


Lymphoid tissue inducer


Interleukin 10


Interleukin-1 beta


2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester


Kynurenine aminotransferases


Killer cell lectin-like receptor B1


Kynurenine 3-monooxygenase




Kynurenic acid


Liver X receptor


Liver X receptor alpha


Liver X receptor beta


Matrix metalloproteinase


Multidrug resistance protein 1


Multiple sclerosis


Nuclear export signal


Nuclear factor 1


Nuclear factor kappa-light-chain-enhancer of activated B cells


Natural killer


Natural killer T


Nitric oxide


Prostaglandin E synthase 3


Polycyclic aromatic hydrocarbons




Peripherial blood mononuclear cells


Planar polychlorinated biphenyls




Toll-like receptor agonist polyinosinic:polycytidylic acid


Peroxisome proliferator-activated receptors


Peroxisome proliferator-activated receptor alpha


PPAR response element


Rheumatoid arthritis




Retinoic acid-related orphan receptor variant 2


RAR-related orphan nuclear receptor gamma t


Shared epitope


Systemic lupus erythematosus


Suppressor of cytokine signaling 3


Sterol regulatory element-binding protein 1


Transactivation domain


T-box expressed in T cells


TATA-box-binding protein


Tryptophan 2,3-dioxygenase


Tumor growth factor beta 1


T helper 17


IL-23 induced Th17 cells


Conventional Th17 cells


2,4,6-Trinitrobenzenesulfonic acid


Tumor necrosis factor alpha


Type 1 regulatory T


Regulatory T cell


UDP glucuronosyltransferase 1 family, polypeptide A1


Hepatitis B virus X-associated protein


Xenobiotic responsive elements





γδ T

Gamma delta T cells



The study was supported by the Hungarian Scientific Research Fund (Grant: OTKA-PD 108297, OTKA-NN 111023 and NK84043and K111958, MEDINPROT, FP7 COST ME HAD BM1202 and FP7 Marie Curie ITN “DYNANO”).


  1. 1.
    Pot C (2012) Aryl hydrocarbon receptor controls regulatory CD4+ T cell function. Swiss Med Wkly 142:w13592. doi: 10.4414/smw.2012.13592 PubMedGoogle Scholar
  2. 2.
    Allan S (2008) T cells: tuning T cells through the aryl hydrocarbon receptor. Nat Rev Immunol 8(5):326CrossRefGoogle Scholar
  3. 3.
    Poland A, Knutson JC (1982) 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22:517–554. doi: 10.1146/ PubMedCrossRefGoogle Scholar
  4. 4.
    Conney AH, Miller EC, Miller JA (1957) Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J Biol Chem 228(2):753–766PubMedGoogle Scholar
  5. 5.
    Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18(3):207–250PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH, Weiner HL, Kuchroo VK (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. doi: 10.1038/ni.1912 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Bennett P, Ramsden DB, Williams AC (1996) Complete structural characterisation of the human aryl hydrocarbon receptor gene. Clin Mol Pathol 49(1):M12–M16PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Dong L, Ma Q, Whitlock JP Jr (1996) DNA binding by the heterodimeric Ah receptor. Relationship to dioxin-induced CYP1A1 transcription in vivo. J Biol Chem 271(14):7942–7948PubMedCrossRefGoogle Scholar
  9. 9.
    Reisz-Porszasz S, Probst MR, Fukunaga BN, Hankinson O (1994) Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Mol Cell Biol 14(9):6075–6086PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O (1995) Identification of functional domains of the aryl hydrocarbon receptor. J Biol Chem 270(49):29270–29278PubMedCrossRefGoogle Scholar
  11. 11.
    Hankinson O (2005) Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor. Arch Biochem Biophys 433(2):379–386. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  12. 12.
    Ko HP, Okino ST, Ma Q, Whitlock JP Jr (1997) Transactivation domains facilitate promoter occupancy for the dioxin-inducible CYP1A1 gene in vivo. Mol Cell Biol 17(7):3497–3507PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kumar MB, Tarpey RW, Perdew GH (1999) Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs. J Biol Chem 274(32):22155–22164PubMedCrossRefGoogle Scholar
  14. 14.
    Kazlauskas A, Poellinger L, Pongratz I (1999) Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor. J Biol Chem 274(19):13519–13524PubMedCrossRefGoogle Scholar
  15. 15.
    Petrulis JR, Perdew GH (2002) The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem Biol Interact 141(1–2):25–40PubMedCrossRefGoogle Scholar
  16. 16.
    Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K (1998) Nuclear localization and export signals of the human aryl hydrocarbon receptor. J Biol Chem 273(5):2895–2904PubMedCrossRefGoogle Scholar
  17. 17.
    White TE, Gasiewicz TA (1993) The human estrogen receptor structural gene contains a DNA sequence that binds activated mouse and human Ah receptors: a possible mechanism of estrogen receptor regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochemical and biophysical research communications 193(3):956–962. doi: 10.1006/bbrc.1993.1718 PubMedCrossRefGoogle Scholar
  18. 18.
    Swanson HI, Chan WK, Bradfield CA (1995) DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. J Biol Chem 270(44):26292–26302PubMedCrossRefGoogle Scholar
  19. 19.
    Whitlock JP Jr (1999) Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol 39(1):103–125PubMedCrossRefGoogle Scholar
  20. 20.
    Shen ES, Whitlock JP Jr (1992) Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor. J Biol Chem 267(10):6815–6819PubMedGoogle Scholar
  21. 21.
    Haarmann-Stemmann T, Abel J (2006) The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function. Biol Chem 387(9):1195–1199. doi: 10.1515/bc.2006.147 PubMedCrossRefGoogle Scholar
  22. 22.
    Baba T, Mimura J, Gradin K, Kuroiwa A, Watanabe T, Matsuda Y, Inazawa J, Sogawa K, Fujii-Kuriyama Y (2001) Structure and expression of the Ah receptor repressor gene. J Biol Chem 276(35):33101–33110. doi: 10.1074/jbc.M011497200 PubMedCrossRefGoogle Scholar
  23. 23.
    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):20–25PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Harper PA, Riddick DS, Okey AB (2006) Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol 72(3):267–279. doi: 10.1016/j.bcp.2006.01.007 PubMedCrossRefGoogle Scholar
  25. 25.
    Fujii-Kuriyama Y, Mimura J (2005) Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochemical and biophysical research communications 338(1):311–317. doi: 10.1016/j.bbrc.2005.08.162 PubMedCrossRefGoogle Scholar
  26. 26.
    Wu HY, Quintana FJ, da Cunha AP, Dake BT, Koeglsperger T, Starossom SC, Weiner HL (2011) In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PLoS One 6(8):e23618. doi: 10.1371/journal.pone.0023618 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Chen PH, Chang H, Chang JT, Lin P (2012) Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer. Oncogene 31(20):2555–2565. doi: 10.1038/onc.2011.438 PubMedCrossRefGoogle Scholar
  28. 28.
    Cunningham M, Gilkeson G (2011) Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 40(1):66–73. doi: 10.1007/s12016-010-8203-5 PubMedCrossRefGoogle Scholar
  29. 29.
    Apelgren LD, Bailey DL, Fouts RL, Short L, Bryan N, Evans GF, Sandusky GE, Zuckerman SH, Glasebrook A, Bumol TF (1996) The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice. Cell Immunol 173(1):55–63. doi: 10.1006/cimm.1996.0251 PubMedCrossRefGoogle Scholar
  30. 30.
    Svenson JL, EuDaly J, Ruiz P, Korach KS, Gilkeson GS (2008) Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol 128(2):259–268. doi: 10.1016/j.clim.2008.03.508 PubMedCrossRefGoogle Scholar
  31. 31.
    Swedenborg E, Pongratz I (2010) AhR and ARNT modulate ER signaling. Toxicology 268(3):132–138. doi: 10.1016/j.tox.2009.09.007 PubMedCrossRefGoogle Scholar
  32. 32.
    Matthews J, Gustafsson JA (2006) Estrogen receptor and aryl hydrocarbon receptor signaling pathways. Nucl Recept Signal 4:e016. doi: 10.1621/nrs.04016 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Safe S, Wormke M (2003) Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem Res Toxicol 16(7):807–816. doi: 10.1021/tx034036r PubMedCrossRefGoogle Scholar
  34. 34.
    Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber DA, Kalnins RP, Frauson LE, Park CN, Barnard SD, Hummel RA, Humiston CG (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(2):279–303PubMedCrossRefGoogle Scholar
  35. 35.
    Abdelrahim M, Ariazi E, Kim K, Khan S, Barhoumi R, Burghardt R, Liu S, Hill D, Finnell R, Wlodarczyk B, Jordan VC, Safe S (2006) 3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha. Cancer Res 66(4):2459–2467. doi: 10.1158/0008-5472.can-05-3132 PubMedCrossRefGoogle Scholar
  36. 36.
    Ricci MS, Toscano DG, Mattingly CJ, Toscano WA Jr (1999) Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. J Biol Chem 274(6):3430–3438PubMedCrossRefGoogle Scholar
  37. 37.
    Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S (2003) The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol 23(6):1843–1855PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Ohtake F, Fujii-Kuriyama Y, Kawajiri K, Kato S (2011) Cross-talk of dioxin and estrogen receptor signals through the ubiquitin system. J Steroid Biochem Mol Biol 127(1–2):102–107. doi: 10.1016/j.jsbmb.2011.03.007 PubMedCrossRefGoogle Scholar
  39. 39.
    Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT (2003) Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 144(8):3382–3398. doi: 10.1210/en.2003-0192 PubMedCrossRefGoogle Scholar
  40. 40.
    Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S (2003) Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423(6939):545–550. doi: 10.1038/nature01606 PubMedCrossRefGoogle Scholar
  41. 41.
    Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9(9):1033–1045PubMedCrossRefGoogle Scholar
  42. 42.
    Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M (1994) A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 14(10):7025–7035PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272(6):3137–3140PubMedCrossRefGoogle Scholar
  44. 44.
    Cui G, Qin X, Wu L, Zhang Y, Sheng X, Yu Q, Sheng H, Xi B, Zhang JZ, Zang YQ (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Investig 121(2):658–670. doi: 10.1172/jci42974 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Walcher D, Kummel A, Kehrle B, Bach H, Grub M, Durst R, Hombach V, Marx N (2006) LXR activation reduces proinflammatory cytokine expression in human CD4-positive lymphocytes. Arterioscler Thromb Vasc Biol 26(5):1022–1028. doi: 10.1161/01.ATV.0000210278.67076.8f PubMedCrossRefGoogle Scholar
  46. 46.
    Fallone F, Villard PH, Decome L, Seree E, Meo M, Chacon C, Durand A, Barra Y, Lacarelle B (2005) PPAR alpha activation potentiates AhR-induced CYP1A1 expression. Toxicology 216(2–3):122–128. doi: 10.1016/j.tox.2005.07.020 PubMedCrossRefGoogle Scholar
  47. 47.
    Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH (2003) Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2. J Biol Chem 278(7):4467–4473. doi: 10.1074/jbc.M211261200 PubMedCrossRefGoogle Scholar
  48. 48.
    Seree E, Villard PH, Pascussi JM, Pineau T, Maurel P, Nguyen QB, Fallone F, Martin PM, Champion S, Lacarelle B, Savouret JF, Barra Y (2004) Evidence for a new human CYP1A1 regulation pathway involving PPAR-alpha and 2 PPRE sites. Gastroenterology 127(5):1436–1445PubMedCrossRefGoogle Scholar
  49. 49.
    Chen CL, Brodie AE, Hu CY (1997) CCAAT/enhancer-binding protein beta is not affected by tetrachlorodibenzo-p-dioxin (TCDD) inhibition of 3T3-L1 preadipocyte differentiation. Obes Res 5(2):146–152PubMedCrossRefGoogle Scholar
  50. 50.
    Jana NR, Sarkar S, Ishizuka M, Yonemoto J, Tohyama C, Sone H (1999) Cross-talk between 2,3,7,8-tetrachlorodibenzo-p-dioxin and testosterone signal transduction pathways in LNCaP prostate cancer cells. Biochemical and biophysical research communications 256(3):462–468. doi: 10.1006/bbrc.1999.0367 PubMedCrossRefGoogle Scholar
  51. 51.
    Ghotbaddini M, Powell JB (2015) The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells. Int J Environ Res Public Health 12(7):7506–7518. doi: 10.3390/ijerph120707506 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tian Y, Ke S, Denison MS, Rabson AB, Gallo MA (1999) Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity. J Biol Chem 274(1):510–515PubMedCrossRefGoogle Scholar
  53. 53.
    Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE (2000) The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19(48):5498–5506. doi: 10.1038/sj.onc.1203945 PubMedCrossRefGoogle Scholar
  54. 54.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240. doi: 10.1084/jem.20041257 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19(6):652–657. doi: 10.1016/j.coi.2007.07.020 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gunimaladevi I, Savan R, Sakai M (2006) Identification, cloning and characterization of interleukin-17 and its family from zebrafish. Fish Shellfish Immunol 21(4):393–403. doi: 10.1016/j.fsi.2006.01.004 PubMedCrossRefGoogle Scholar
  57. 57.
    Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21(4):467–476. doi: 10.1016/j.immuni.2004.08.018 PubMedCrossRefGoogle Scholar
  58. 58.
    McKenzie BS, Kastelein RA, Cua DJ (2006) Understanding the IL-23-IL-17 immune pathway. Trends Immunol 27(1):17–23. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  59. 59.
    Attur MG, Patel RN, Abramson SB, Amin AR (1997) Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage. Arthritis Rheum 40(6):1050–1053. doi: 10.1002/art.1780400609 PubMedCrossRefGoogle Scholar
  60. 60.
    Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L, Kasman I, Winer J, Modrusan Z, Danilenko DM, Ouyang W (2007) The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol (Baltimore, Md: 1950) 178(4):2229–2240Google Scholar
  61. 61.
    Kim K-W, Kim H-R, Park J-Y, Park J-S, Oh H-J, Woo Y-J, Park M-K, Cho M-L, Lee S-H (2012) Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis Rheum 64(4):1015–1023. doi: 10.1002/art.33446 PubMedCrossRefGoogle Scholar
  62. 62.
    Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408(6808):57–63. doi: 10.1038/35040504 PubMedCrossRefGoogle Scholar
  63. 63.
    Pelletier M, Bouchard A, Girard D (2004) In vivo and in vitro roles of IL-21 in inflammation. J Immunol (Baltimore, Md: 1950) 173(12):7521–7530Google Scholar
  64. 64.
    Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194(1–2):54–61. doi: 10.1016/j.jneuroim.2007.11.006 PubMedCrossRefGoogle Scholar
  65. 65.
    Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 13(10):1173–1175PubMedCrossRefGoogle Scholar
  66. 66.
    Bogaert S, Laukens D, Peeters H, Melis L, Olievier K, Boon N, Verbruggen G, Vandesompele J, Elewaut D, De Vos M (2010) Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease. BMC Immunology 11(1):1–11. doi: 10.1186/1471-2172-11-61 CrossRefGoogle Scholar
  67. 67.
    Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science (New York, NY) 314(5804):1461–1463CrossRefGoogle Scholar
  68. 68.
    Chen XQ, Yu YC, Deng HH, Sun JZ, Dai Z, Wu YW, Yang M (2010) Plasma IL-17A is increased in new-onset SLE patients and associated with disease activity. J Clin Immunol 30(2):221–225PubMedCrossRefGoogle Scholar
  69. 69.
    Zhao Y, Yang J, Gao Y, Guo W (2010) Th17 Immunity in Patients with Allergic Asthma. Int Arch Allergy Immunol 151(4):297–307PubMedCrossRefGoogle Scholar
  70. 70.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238. doi: 10.1038/nature04753 PubMedCrossRefGoogle Scholar
  71. 71.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-[beta] induces development of the TH17 lineage. Nature 441(7090):231–234. doi:
  72. 72.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189. doi: 10.1016/j.immuni.2006.01.001 PubMedCrossRefGoogle Scholar
  73. 73.
    Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30(4):576–587. doi: 10.1016/j.immuni.2009.02.007 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells. Cell 126(6):1121–1133. doi: 10.1016/j.cell.2006.07.035 PubMedCrossRefGoogle Scholar
  75. 75.
    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39. doi: 10.1016/j.immuni.2007.11.016 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T, Sakaguchi N, Sakaguchi S (2007) Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 204(12):2803–2812. doi: 10.1084/jem.20071397 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8 (9):967–974. doi:
  78. 78.
    Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30(1):92–107. doi: 10.1016/j.immuni.2008.11.005 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467(7318):967–971. doi: 10.1038/nature09447 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263. doi: 10.1038/ni.1993 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, Rodolico G, Querci V, Abbate G, Angeli R, Berrino L, Fambrini M, Caproni M, Tonelli F, Lazzeri E, Parronchi P, Liotta F, Maggi E, Romagnani S, Annunziato F (2008) Human interleukin 17-producing cells originate from a CD161+ CD4+ T cell precursor. J Exp Med 205(8):1903–1916. doi: 10.1084/jem.20080397 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Lanier LL, Chang C, Phillips JH (1994) Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol (Baltimore, Md: 1950) 153(6):2417–2428Google Scholar
  83. 83.
    Maggi L, Santarlasci V, Capone M, Peired A, Frosali F, Crome SQ, Querci V, Fambrini M, Liotta F, Levings MK, Maggi E, Cosmi L, Romagnani S, Annunziato F (2010) CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol 40(8):2174–2181. doi: 10.1002/eji.200940257 PubMedCrossRefGoogle Scholar
  84. 84.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1 beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8(9):942–949. doi: 10.1038/ni1496 PubMedCrossRefGoogle Scholar
  85. 85.
    Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56(9):2936–2946. doi: 10.1002/art.22866 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8(9):950–957. doi: 10.1038/ni1497 PubMedCrossRefGoogle Scholar
  87. 87.
    Santarlasci V, Maggi L, Capone M, Frosali F, Querci V, De Palma R, Liotta F, Cosmi L, Maggi E, Romagnani S, Annunziato F (2009) TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol 39(1):207–215. doi: 10.1002/eji.200838748 PubMedCrossRefGoogle Scholar
  88. 88.
    Li Y, David EA, Clare B-A, William DH, Estelle B, Mohamed O, Vijay KK, David AH (2008) IL-21 and TGF-beta are required for differentiation of human TH17 cells. Nature 454(7202):350–352. doi: 10.1038/nature07021 CrossRefGoogle Scholar
  89. 89.
    Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8(6):639–646. doi: 10.1038/ni1467 PubMedCrossRefGoogle Scholar
  90. 90.
    Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204(8):1849–1861. doi: 10.1084/jem.20070663 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S (2009) Human Th17 cells: are they different from murine Th17 cells? Eur J Immunol 39(3):637–640. doi: 10.1002/eji.200839050 PubMedCrossRefGoogle Scholar
  92. 92.
    Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanzavecchia A, Sallusto F (2012) Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 484(7395):514–518. doi: 10.1038/nature10957 PubMedCrossRefGoogle Scholar
  93. 93.
    Eberl G, Littman DR (2004) Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Science (New York, NY) 305(5681):248–251. doi: 10.1126/science.1096472 CrossRefGoogle Scholar
  94. 94.
    Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science (New York, NY) 288(5475):2369–2373CrossRefGoogle Scholar
  95. 95.
    Medvedev A, Chistokhina A, Hirose T, Jetten AM (1997) Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene. Genomics 46(1):93–102. doi: 10.1006/geno.1997.4980 PubMedCrossRefGoogle Scholar
  96. 96.
    Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci USA 97(18):10132–10137PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol (Baltimore, Md: 1950) 178(8):4901–4907Google Scholar
  98. 98.
    Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282(13):9358–9363. doi: 10.1074/jbc.C600321200 PubMedCrossRefGoogle Scholar
  99. 99.
    Chen Z, Laurence A, O’Shea JJ (2007) Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol 19(6):400–408. doi: 10.1016/j.smim.2007.10.015 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240. doi: 10.1038/nature06878 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Hirahara K, Ghoreschi K, Laurence A, Yang XP, Kanno Y, O’Shea JJ (2010) Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev 21(6):425–434. doi: 10.1016/j.cytogfr.2010.10.006 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9(6):641–649. doi: 10.1038/ni.1610 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Unutmaz D (2009) RORC2: the master of human Th17 cell programming. Eur J Immunol 39(6):1452–1455. doi: 10.1002/eji.200939540 PubMedCrossRefGoogle Scholar
  104. 104.
    Crome SQ, Wang AY, Kang CY, Levings MK (2009) The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells. Eur J Immunol 39(6):1480–1493. doi: 10.1002/eji.200838908 PubMedCrossRefGoogle Scholar
  105. 105.
    Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, Pierce R, McClanahan TK, Sadekova S, de Waal Malefyt R (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol (Baltimore, Md: 1950) 185(1):679–687. doi: 10.4049/jimmunol.1000366
  106. 106.
    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. doi: 10.1016/j.taap.2007.01.014 PubMedCrossRefGoogle Scholar
  107. 107.
    Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2008) Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA 105(28):9721–9726. doi: 10.1073/pnas.0804231105 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453(7191):65–71. doi: 10.1038/nature06880 PubMedCrossRefGoogle Scholar
  109. 109.
    Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld J-C, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. doi:
  110. 110.
    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. doi: 10.1084/jem.20081438 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Zenewicz LA, Flavell RA (2011) Recent advances in IL-22 biology. Int Immunol 23(3):159–163. doi: 10.1093/intimm/dxr001 PubMedCrossRefGoogle Scholar
  112. 112.
    Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K, Yasutomo K (2010) Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 107(13):5943–5948. doi: 10.1073/pnas.0911755107 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ho PP, Steinman L (2008) The aryl hydrocarbon receptor: a regulator of Th17 and Treg cell development in disease. Cell Res 18(6):605–608PubMedCrossRefGoogle Scholar
  114. 114.
    Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ (1995) Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science (New York, NY) 268(5211):722–726CrossRefGoogle Scholar
  115. 115.
    Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140(1):173–179. doi: 10.1006/taap.1996.0210 PubMedCrossRefGoogle Scholar
  116. 116.
    Dolwick KM, Schmidt JV, Carver LA, Swanson HI, Bradfield CA (1993) Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol 44(5):911–917PubMedGoogle Scholar
  117. 117.
    Jiang YZ, Wang K, Fang R, Zheng J (2010) Expression of aryl hydrocarbon receptor in human placentas and fetal tissues. J Histochem Cytochem 58(8):679–685. doi: 10.1369/jhc.2010.955955 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Kobayashi S, Okamoto H, Iwamoto T, Toyama Y, Tomatsu T, Yamanaka H, Momohara S (2008) A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis. Rheumatology (Oxford) 47(9):1317–1322. doi: 10.1093/rheumatology/ken259 CrossRefGoogle Scholar
  119. 119.
    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. doi: 10.1038/ni.1770 PubMedCrossRefGoogle Scholar
  120. 120.
    Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, Hong SL (2014) Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis. QJM 107(2):107–113. doi: 10.1093/qjmed/hct188 PubMedCrossRefGoogle Scholar
  121. 121.
    Ramirez JM, Brembilla NC, Sorg O, Chicheportiche R, Matthes T, Dayer JM, Saurat JH, Roosnek E, Chizzolini C (2010) Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur J Immunol 40(9):2450–2459. doi: 10.1002/eji.201040461 PubMedCrossRefGoogle Scholar
  122. 122.
    Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A (2011) Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science (New York, NY) 334(6062):1561–1565. doi: 10.1126/science.1214914 CrossRefGoogle Scholar
  123. 123.
    Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009) Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31(2):321–330. doi: 10.1016/j.immuni.2009.06.020 PubMedCrossRefGoogle Scholar
  124. 124.
    Hooper LV (2011) You AhR what you eat: linking diet and immunity. Cell 147(3):489–491. doi: 10.1016/j.cell.2011.10.004 PubMedCrossRefGoogle Scholar
  125. 125.
    Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147(3):629–640. doi: 10.1016/j.cell.2011.09.025 PubMedCrossRefGoogle Scholar
  126. 126.
    Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10(7):479–489. doi: 10.1038/nri2800 PubMedCrossRefGoogle Scholar
  127. 127.
    Crellin NK, Trifari S, Kaplan CD, Cupedo T, Spits H (2010) Human NKp44+ IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J Exp Med 207(2):281–290. doi: 10.1084/jem.20091509 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O’Shea JJ (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206(1):35–41. doi: 10.1084/jem.20072713 PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Okey AB (2007) An aryl hydrocarbon receptor odyssey to the shores of toxicology: the deichmann lecture. International Congress of Toxicology-XI. Toxicol Sci 98(1):5–38PubMedCrossRefGoogle Scholar
  130. 130.
    Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1):102–116. doi: 10.1021/tx7001965 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI (2005) Cutting edge: activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+ CD25+ cells with characteristics of regulatory T cells. J Immunol (Baltimore, Md: 1950) 175(7):4184–4188Google Scholar
  132. 132.
    Tamaki A, Hayashi H, Nakajima H, Takii T, Katagiri D, Miyazawa K, Hirose K, Onozaki K (2004) Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor. Biol Pharm Bull 27(3):407–410PubMedCrossRefGoogle Scholar
  133. 133.
    Sutter TR, Guzman K, Dold KM, Greenlee WF (1991) Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta. Science (New York, NY) 254(5030):415–418Google Scholar
  134. 134.
    Yang JH (1999) Expression of dioxin-responsive genes in human endometrial cells in culture. Biochem Biophys Res Commun 257(2):259–263. doi: 10.1006/bbrc.1999.0451 PubMedCrossRefGoogle Scholar
  135. 135.
    Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, Lee TG, Kang JK, Gasiewicz TA, Ryu SH, Suh PG (2006) Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol 69(6):1871–1878. doi: 10.1124/mol.105.021832 PubMedCrossRefGoogle Scholar
  136. 136.
    Zhao B, Degroot DE, Hayashi A, He G, Denison MS (2010) CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol Sci 117(2):393–403. doi: 10.1093/toxsci/kfq217 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y, Ishikawa T (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 97(2):779–782PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    O’Donnell EF, Saili KS, Koch DC, Kopparapu PR, Farrer D, Bisson WH, Mathew LK, Sengupta S, Kerkvliet NI, Tanguay RL, Kolluri SK (2010) The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One 5(10). doi: 10.1371/journal.pone.0013128
  139. 139.
    Baban B, Liu JY, Mozaffari MS (2012) Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells. Am J Physiol Regul Integr Comp Physiol 303(11):R1136–R1146. doi: 10.1152/ajpregu.00315.2012 PubMedCrossRefGoogle Scholar
  140. 140.
    Song J, Clagett-Dame M, Peterson RE, Hahn ME, Westler WM, Sicinski RR, DeLuca HF (2002) A ligand for the aryl hydrocarbon receptor isolated from lung. Proc Natl Acad Sci USA 99(23):14694–14699. doi: 10.1073/pnas.232562899 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ, Weiner HL (2010) An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 107(48):20768–20773. doi: 10.1073/pnas.1009201107 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Wang C, Ye Z, Kijlstra A, Zhou Y, Yang P (2014) Activation of the aryl hydrocarbon receptor affects activation and function of human monocyte-derived dendritic cells. Clin Exp Immunol 177(2):521–530. doi: 10.1111/cei.12352 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, Zhang C, Hong SL (2014) An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients. Lab Invest 94(5):528–535. doi: 10.1038/labinvest.2014.8 PubMedCrossRefGoogle Scholar
  144. 144.
    Bisht K, Wagner KH, Bulmer AC (2010) Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology 278(1):88–100. doi: 10.1016/j.tox.2009.11.008 PubMedCrossRefGoogle Scholar
  145. 145.
    Rannug A, Rannug U, Rosenkranz HS, Winqvist L, Westerholm R, Agurell E, Grafstrom AK (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):15422–15427PubMedGoogle Scholar
  146. 146.
    Oberg M, Bergander L, Hakansson H, Rannug U, Rannug A (2005) Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity. Toxicol Sci 85(2):935–943. doi: 10.1093/toxsci/kfi154 PubMedCrossRefGoogle Scholar
  147. 147.
    Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH (2007) Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396(1):203–213. doi: 10.1016/j.gene.2007.04.010 PubMedCrossRefGoogle Scholar
  148. 148.
    Kincses ZT, Toldi J, Vecsei L (2010) Kynurenines, neurodegeneration and Alzheimer’s disease. J Cell Mol Med 14(8):2045–2054. doi: 10.1111/j.1582-4934.2010.01123.x PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    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 (Baltimore, Md: 1950) 185(6):3190–3198. doi: 10.4049/jimmunol.0903670
  150. 150.
    DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS, Laurenzana EM, Omiecinski CJ, Perdew GH (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(1):89–97. doi: 10.1093/toxsci/kfq024 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Alberati-Giani D, Cesura AM, Broger C, Warren WD, Rover S, Malherbe P (1997) Cloning and functional expression of human kynurenine 3-monooxygenase. FEBS Lett 410(2–3):407–412PubMedCrossRefGoogle Scholar
  152. 152.
    Stephens GL, Wang Q, Swerdlow B, Bhat G, Kolbeck R, Fung M (2013) Kynurenine 3-monooxygenase mediates inhibition of Th17 differentiation via catabolism of endogenous aryl hydrocarbon receptor ligands. Eur J Immunol 43(7):1727–1734. doi: 10.1002/eji.201242779 PubMedCrossRefGoogle Scholar
  153. 153.
    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci. doi: 10.1073/pnas.0812874106 PubMedPubMedCentralGoogle Scholar
  154. 154.
    Schroeder JC, Dinatale BC, Murray IA, Flaveny CA, Liu Q, Laurenzana EM, Lin JM, Strom SC, Omiecinski CJ, Amin S, Perdew GH (2010) The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49(2):393–400. doi: 10.1021/bi901786x PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Banoglu E, Jha GG, King RS (2001) Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur J Drug Metab Pharmacokinet 26(4):235–240PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Hwang S-J, Hwang Y-J, Yun M-O, Kim J-H, Oh G-S, Park J-H (2013) Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis. Toxicol Lett 220(2):109–117. doi: 10.1016/j.toxlet.2013.04.016 PubMedCrossRefGoogle Scholar
  157. 157.
    Schroecksnadel K, Kaser S, Ledochowski M, Neurauter G, Mur E, Herold M, Fuchs D (2003) Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol 30(9):1935–1939PubMedGoogle Scholar
  158. 158.
    Rouse M, Singh NP, Nagarkatti PS, Nagarkatti M (2013) Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells. Br J Pharmacol 169(6):1305–1321. doi: 10.1111/bph.12205 PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Aggarwal BB, Ichikawa H (2005) Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell cycle (Georgetown, Tex) 4(9):1201–1215Google Scholar
  160. 160.
    Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75(4):787–809. doi: 10.1016/j.bcp.2007.08.016 PubMedCrossRefGoogle Scholar
  161. 161.
    Nishiumi S, K-i Yoshida, Ashida H (2007) Curcumin suppresses the transformation of an aryl hydrocarbon receptor through its phosphorylation. Arch Biochem Biophys 466(2):267–273. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  162. 162.
    Ciolino HP, Daschner PJ, Wang TTY, Yeh GC (1998) Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells. Biochem Pharmacol 56(2):197–206. doi: 10.1016/S0006-2952(98)00143-9 PubMedCrossRefGoogle Scholar
  163. 163.
    Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65(11):1631–1652. doi: 10.1007/s00018-008-7452-4 PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Abe Y, Hashimoto S, Horie T (1999) Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39(1):41–47. doi: 10.1006/phrs.1998.0404 PubMedCrossRefGoogle Scholar
  165. 165.
    Chakravarti N, Myers JN, Aggarwal BB (2006) Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). Int J Cancer 119(6):1268–1275. doi: 10.1002/ijc.21967 PubMedCrossRefGoogle Scholar
  166. 166.
    Casper RF, Quesne M, Rogers IM, Shirota T, Jolivet A, Milgrom E, Savouret JF (1999) Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol Pharmacol 56(4):784–790PubMedGoogle Scholar
  167. 167.
    Lanzilli G, Cottarelli A, Nicotera G, Guida S, Ravagnan G, Fuggetta MP (2012) Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 35(1):240–248. doi: 10.1007/s10753-011-9310-z PubMedCrossRefGoogle Scholar
  168. 168.
    Fabris S, Momo F, Ravagnan G, Stevanato R (2008) Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes. Biophys Chem 135(1–3):76–83. doi: 10.1016/j.bpc.2008.03.005 PubMedCrossRefGoogle Scholar
  169. 169.
    Li T, Wang W, Chen H, Li T, Ye L (2010) Evaluation of anti-leukemia effect of resveratrol by modulating SATA3 signaling. Int Immunopharmacol 10(1):18–25. doi: 10.1016/j.intimp.2009.09.009 PubMedCrossRefGoogle Scholar
  170. 170.
    Singh NP, Hegde VL, Hofseth LJ, Nagarkatti M, Nagarkatti P (2007) Resveratrol (trans-3,5,4′-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol 72(6):1508–1521. doi: 10.1124/mol.107.038984 PubMedCrossRefGoogle Scholar
  171. 171.
    Imler TJ Jr, Petro TM (2009) Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+ IL-10+ T cells, CD4(−) IFN-gamma+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 9(1):134–143. doi: 10.1016/j.intimp.2008.10.015 PubMedCrossRefGoogle Scholar
  172. 172.
    Lu B, Solomon DH, Costenbader KH, Keenan BT, Chibnik LB, Karlson EW (2010) Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis. Arthritis Rheum 62(12):3554–3559. doi: 10.1002/art.27739 PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Hollman PC, Katan MB (1997) Absorption, metabolism and health effects of dietary flavonoids in man. Biomed Pharm 51(8):305–310Google Scholar
  174. 174.
    Zhang S, Qin C, Safe SH (2003) Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect 111(16):1877–1882PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Cazarolli LH, Zanatta L, Alberton EH, Figueiredo MS, Folador P, Damazio RG, Pizzolatti MG, Silva FR (2008) Flavonoids: prospective drug candidates. Mini Rev Med Chem 8(13):1429–1440PubMedCrossRefGoogle Scholar
  176. 176.
    Kasai A, Hiramatsu N, Hayakawa K, Yao J, Kitamura M (2008) Blockade of the dioxin pathway by herbal medicine Formula Bupleuri Minor: identification of active entities for suppression of AhR activation. Biol Pharm Bull 31(5):838–846PubMedCrossRefGoogle Scholar
  177. 177.
    Ashida H (2000) Suppressive effects of flavonoids on dioxin toxicity. BioFactors (Oxford, England) 12(1–4):201–206Google Scholar
  178. 178.
    Yang J, Yang X, Chu Y, Li M (2011) Identification of Baicalin as an immunoregulatory compound by controlling T(H)17 cell differentiation. PLoS One 6(2):e17164. doi: 10.1371/journal.pone.0017164 PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Gasiewicz TA, Rucci G (1991) Alpha-naphthoflavone acts as an antagonist of 2,3,7, 8-tetrachlorodibenzo-p-dioxin by forming an inactive complex with the Ah receptor. Mol Pharmacol 40(5):607–612PubMedGoogle Scholar
  180. 180.
    Moura-Alves P, Fae K, Houthuys E, Dorhoi A, Kreuchwig A, Furkert J, Barison N, Diehl A, Munder A, Constant P, Skrahina T, Guhlich-Bornhof U, Klemm M, Koehler AB, Bandermann S, Goosmann C, Mollenkopf HJ, Hurwitz R, Brinkmann V, Fillatreau S, Daffe M, Tummler B, Kolbe M, Oschkinat H, Krause G, Kaufmann SH (2014) AhR sensing of bacterial pigments regulates antibacterial defence. Nature 512(7515):387–392. doi: 10.1038/nature13684 PubMedCrossRefGoogle Scholar
  181. 181.
    Baka Z, Buzas E, Nagy G (2009) Rheumatoid arthritis and smoking: putting the pieces together. Arthritis Res Ther 11(4):238. doi: 10.1186/ar2751 PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L (2004) A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 50(10):3085–3092. doi: 10.1002/art.20553 PubMedCrossRefGoogle Scholar
  183. 183.
    Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54(1):38–46. doi: 10.1002/art.21575 PubMedCrossRefGoogle Scholar
  184. 184.
    Benson JM, Shepherd DM (2011) Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn’s disease. Toxicol Sci 120(1):68–78. doi: 10.1093/toxsci/kfq360 PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Kazantseva MG, Highton J, Stamp LK, Hessian PA (2012) Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis. Arthritis Res Ther 14(5):R208. doi: 10.1186/ar4046 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Xuzhu G, Komai-Koma M, Leung BP, Howe HS, McSharry C, McInnes IB, Xu D (2012) Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis 71(1):129–135. doi: 10.1136/ard.2011.149831 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Eszter Baricza
    • 1
  • Viola Tamási
    • 1
  • Nikolett Marton
    • 1
  • Edit I. Buzás
    • 1
  • György Nagy
    • 1
    • 2
    Email author
  1. 1.Department of Genetics, Cell and ImmunobiologySemmelweis UniversityBudapestHungary
  2. 2.Department of RheumatologySemmelweis UniversityBudapestHungary

Personalised recommendations