芳香烃受体在炎症性皮肤病中的研究进展
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摘要
芳香烃受体是一种配体激活转录因子,具有诱导多种重要的外源性细胞色素P450酶作用。近年来研究发现,芳香烃受体不仅可介导化学物质的毒性反应,它还广泛存在于人体的各种皮肤组织细胞,例如角质形成细胞及皮脂腺细胞,该受体可参与许多重要的生物学过程,如细胞增殖和分化、免疫调节和炎症反应的发生。近期有研究表明,芳香烃受体的活化对炎症性皮肤病有益,例如特应性皮炎和银屑病等。因此,芳香烃受体可能成为潜在的皮肤病治疗靶点。
The aryl hydrocarbon receptor( AhR) is a ligand—activated transcription factor capable of inducing multiple important exogenous cytochrome P450 enzymes. It not only mediates the toxicity of exogenous chemical agents,but also expresses in all cell types such as keratinocytes and sebocytes. It is a central player in many important biological processes such as cell proliferation and differentiation,immune regulation and inflammatory response. Recent studies indicate that the AhR activation is beneficial to inflammatory skin diseases such as atopic dermatitis and psoriasis,etc.Therefore,AhR seems to be an attractive therapeutic target for its multifaceted role in skin diseases.
The aryl hydrocarbon receptor( AhR) is a ligand—activated transcription factor capable of inducing multiple important exogenous cytochrome P450 enzymes. It not only mediates the toxicity of exogenous chemical agents,but also expresses in all cell types such as keratinocytes and sebocytes. It is a central player in many important biological processes such as cell proliferation and differentiation,immune regulation and inflammatory response. Recent studies indicate that the AhR activation is beneficial to inflammatory skin diseases such as atopic dermatitis and psoriasis,etc.Therefore,AhR seems to be an attractive therapeutic target for its multifaceted role in skin diseases.
引文
[1]Esser C.Biology and function of the aryl hydrocarbon receptor:report of an international and interdisciplinary conference[J].Archives of Toxicology,2012,86(8):1323-1329.
[2]Nebert DW,Karp CL.Endogenousfunctions of the aryl hydrocarbon receptor(AHR):Intersection of cytochrome P450 1(CYP1)-metabolized eicosanoids and AHR biology[J].J Biol Chem,2008,283(52):36061-36065.
[3]Fukunaga BN,Probst MR,Reiszporszasz S,et al.Identification offunctional domains of the Aryl-Hydrocarbon Receptor[J].J Biol Chem,1995,270(49):29270-29278.
[4]Henklova P,Vrzal R,Ulrichova J,et al.Role of mitogen-activated protein kinases in aryl hydrocarbon receptor signaling[J].Chem-Biol Interact,2008,172(2):93-104.
[5]Pollenz RS,Buggy C.Ligand-dependent and-independent degradation of the human aryl hydrocarbon receptor(hAHR)in cell culture models[J].Chem-Biol Interact,2006,164(1-2):49-59.
[6]Ma Q.Influence of light on aryl hydrocarbon receptor signaling and consequences in drug metabolism,physiology and disease[J].Expert Opin Drug Met,2011,7(10):1267-1293.
[7]Napolitano M,Patruno C.Aryl hydrocarbon receptor(AhR)a possible target for the treatment of skin disease[J].Med Hypotheses,2018,116(1):96-100.
[8]Haarmann-Stemmann T,Esser C,Krutmann J.The Janus-Facedrole of aryl hydrocarbon receptor signaling in the skin:Consequences for prevention and treatment of skin disorders[J].Journal of Investigative Dermatology,2015,135(11):2572-76.
[9]Denison MS,Soshilov AA,He GC,et al.Exactly thesame but different:Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon(Dioxin)receptor[J].Toxicol Sci,2011,124(1):1-22.
[10]Wincent E,Bengtsson J,Bardbori AM,et al.Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZas a mechanism for activation of the aryl hydrocarbon receptor[J].P Natl Acad Sci USA,2012,109(12):4479-4484.
[11]Hollingshead BD,Beischlag TV,Dinatale BC,et al.Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells[J].Cancer Res,2008,68(10):3609-3617.
[12]Roelofzen JHJ,van der Valk PGM,Godschalk R,et al.DNA adducts in skin biopsies and 1-hydroxypyrene in urine of psoriasis patients and healthy volunteers following treatment with coal tar[J].Toxicol Lett,2012,213(1):39-44.
[13]Innocentin YLS,Withers DR,Roberts NA,et al.Exogenousstimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation[J].Cell,2011,147(3):629-640.
[14]Furue M,Tsuji G,Mitoma C,et al.Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor[J].J Dermatol Sci,2015,80(2):83-88.
[15]Tsuji G,Hashimoto-Hachiya A,Kiyomatsu-Oda M,et al.Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis[J].Cell Death Dis,2017,8(7):e2931.
[16]van den Bogaard EH,Bergboer JG,Vonk-Bergers M,et al.Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis[J].J Clin Invest,2013,123(2):9179-27.
[17]Bissonnette R,Poulin Y,Zhou Y,et al.Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis:results from a 12-week,multicentre,randomized,placebo-controlled double-blind trial[J].Br J Dermatol,2012,166(4):853-860.
[18]Quintana FJ.The aryl hydrocarbon receptor:a molecular pathway for the environmental control of the immune response[J].Immunology,2013,138(3):183-189.
[19]Di Meglio P,Duarte JH,Ahlfors H,et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions[J].Immunity,2014,40(6):989-1001.
[20]Zhao L,Chen X,Cai L,et al.Randomized,double-blind,placebocontrolled,multiple-dose study of the safety,tolerability and pharmacokinetics of benvitimod,a candidate drug for the treatment of psoriasis[J].J Clin Pharm Ther,2014,39(4):418-23.
[21]Boniface K,Seneschal J,Taieb A,et al.Vitiligo therapy:restoring immune privilege?[J].Exp Dermatol,2017,26(7):635-636.
[22]Luecke S,Backlund M,Jux B,et al.The aryl hydrocarbon receptor(AHR),a novel regulator of human melanogenesis[J].Pigment Cell Melanoma Res,2010,23(6):828-833.
[23]Ju Q,Fimmel S,Hinz N,et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro[J].Exp Dermatol,2011,20(4):320-325.
[24]Zouboulis CC,Adjaye J,Akamatsu H,et al.Human skin stem cells and the ageing process[J].Exp Gerontol,2008,43(11):986-997.
[25]Saurat JH,Kaya G,Saxer-Sekulic N,et al.The cutaneous lesions of dioxin exposure:lessons from the poisoning of Victor Yushchenko[J].Toxicol Sci,2012,125(1):310-317.
[26]Fabbrocini G,Kaya G,Caseiro Silverio P,et al.Arylhydrocarbon receptor activation in acne vulgaris skin:A case series from the region of naples,Italy[J].Dermatology,2015,231(4):334-338.
[27]Mastrangelo G,Veller Fornasa C,Pavanello S,et al.Polyaromatic hydrocarbons administered in humans by dermal route increase total Ig E[J].Int J Immunopathol Pharmacol,2003,16(2):145-150.
[28]Wincent E,Amini N,Luecke S,et al.The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans[J].J Biol Chem,2009,284(5):2690-2696.
[29]Murota H,Izumi M,Abd El-Latif MI,et al.Artemin causes hypersensitivity to warm sensation,mimicking warmth-provoked pruritus in atopic dermatitis[J].J Allergy Clin Immunol,2012,130(3):671-682 e4.
[2]Nebert DW,Karp CL.Endogenousfunctions of the aryl hydrocarbon receptor(AHR):Intersection of cytochrome P450 1(CYP1)-metabolized eicosanoids and AHR biology[J].J Biol Chem,2008,283(52):36061-36065.
[3]Fukunaga BN,Probst MR,Reiszporszasz S,et al.Identification offunctional domains of the Aryl-Hydrocarbon Receptor[J].J Biol Chem,1995,270(49):29270-29278.
[4]Henklova P,Vrzal R,Ulrichova J,et al.Role of mitogen-activated protein kinases in aryl hydrocarbon receptor signaling[J].Chem-Biol Interact,2008,172(2):93-104.
[5]Pollenz RS,Buggy C.Ligand-dependent and-independent degradation of the human aryl hydrocarbon receptor(hAHR)in cell culture models[J].Chem-Biol Interact,2006,164(1-2):49-59.
[6]Ma Q.Influence of light on aryl hydrocarbon receptor signaling and consequences in drug metabolism,physiology and disease[J].Expert Opin Drug Met,2011,7(10):1267-1293.
[7]Napolitano M,Patruno C.Aryl hydrocarbon receptor(AhR)a possible target for the treatment of skin disease[J].Med Hypotheses,2018,116(1):96-100.
[8]Haarmann-Stemmann T,Esser C,Krutmann J.The Janus-Facedrole of aryl hydrocarbon receptor signaling in the skin:Consequences for prevention and treatment of skin disorders[J].Journal of Investigative Dermatology,2015,135(11):2572-76.
[9]Denison MS,Soshilov AA,He GC,et al.Exactly thesame but different:Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon(Dioxin)receptor[J].Toxicol Sci,2011,124(1):1-22.
[10]Wincent E,Bengtsson J,Bardbori AM,et al.Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZas a mechanism for activation of the aryl hydrocarbon receptor[J].P Natl Acad Sci USA,2012,109(12):4479-4484.
[11]Hollingshead BD,Beischlag TV,Dinatale BC,et al.Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells[J].Cancer Res,2008,68(10):3609-3617.
[12]Roelofzen JHJ,van der Valk PGM,Godschalk R,et al.DNA adducts in skin biopsies and 1-hydroxypyrene in urine of psoriasis patients and healthy volunteers following treatment with coal tar[J].Toxicol Lett,2012,213(1):39-44.
[13]Innocentin YLS,Withers DR,Roberts NA,et al.Exogenousstimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation[J].Cell,2011,147(3):629-640.
[14]Furue M,Tsuji G,Mitoma C,et al.Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor[J].J Dermatol Sci,2015,80(2):83-88.
[15]Tsuji G,Hashimoto-Hachiya A,Kiyomatsu-Oda M,et al.Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis[J].Cell Death Dis,2017,8(7):e2931.
[16]van den Bogaard EH,Bergboer JG,Vonk-Bergers M,et al.Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis[J].J Clin Invest,2013,123(2):9179-27.
[17]Bissonnette R,Poulin Y,Zhou Y,et al.Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis:results from a 12-week,multicentre,randomized,placebo-controlled double-blind trial[J].Br J Dermatol,2012,166(4):853-860.
[18]Quintana FJ.The aryl hydrocarbon receptor:a molecular pathway for the environmental control of the immune response[J].Immunology,2013,138(3):183-189.
[19]Di Meglio P,Duarte JH,Ahlfors H,et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions[J].Immunity,2014,40(6):989-1001.
[20]Zhao L,Chen X,Cai L,et al.Randomized,double-blind,placebocontrolled,multiple-dose study of the safety,tolerability and pharmacokinetics of benvitimod,a candidate drug for the treatment of psoriasis[J].J Clin Pharm Ther,2014,39(4):418-23.
[21]Boniface K,Seneschal J,Taieb A,et al.Vitiligo therapy:restoring immune privilege?[J].Exp Dermatol,2017,26(7):635-636.
[22]Luecke S,Backlund M,Jux B,et al.The aryl hydrocarbon receptor(AHR),a novel regulator of human melanogenesis[J].Pigment Cell Melanoma Res,2010,23(6):828-833.
[23]Ju Q,Fimmel S,Hinz N,et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro[J].Exp Dermatol,2011,20(4):320-325.
[24]Zouboulis CC,Adjaye J,Akamatsu H,et al.Human skin stem cells and the ageing process[J].Exp Gerontol,2008,43(11):986-997.
[25]Saurat JH,Kaya G,Saxer-Sekulic N,et al.The cutaneous lesions of dioxin exposure:lessons from the poisoning of Victor Yushchenko[J].Toxicol Sci,2012,125(1):310-317.
[26]Fabbrocini G,Kaya G,Caseiro Silverio P,et al.Arylhydrocarbon receptor activation in acne vulgaris skin:A case series from the region of naples,Italy[J].Dermatology,2015,231(4):334-338.
[27]Mastrangelo G,Veller Fornasa C,Pavanello S,et al.Polyaromatic hydrocarbons administered in humans by dermal route increase total Ig E[J].Int J Immunopathol Pharmacol,2003,16(2):145-150.
[28]Wincent E,Amini N,Luecke S,et al.The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans[J].J Biol Chem,2009,284(5):2690-2696.
[29]Murota H,Izumi M,Abd El-Latif MI,et al.Artemin causes hypersensitivity to warm sensation,mimicking warmth-provoked pruritus in atopic dermatitis[J].J Allergy Clin Immunol,2012,130(3):671-682 e4.