title: Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions.
abstract: Occupational and environmental exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested to provoke inflammatory and/or allergic disorders, including asthma, rhinitis, and dermatitis. The molecular mechanisms of this PAH-mediated inflammation remain to be clarified. Previous studies implied the involvement of PAHs as irritants and allergens, with the reactive oxygen species generated from the oxygenated PAHs believed to be an exacerbating factor. It is also possible that PAHs contribute to the pathogenesis through activation of aryl-hydrocarbon receptor (AhR)-mediated transcription, since PAHs are potent inducers of the AhR. To address this point, we generated transgenic mouse lines expressing the constitutive active form of the AhR in keratinocytes. In these lines of mice, the AhR activity was constitutively enhanced in the absence of ligands, so that any other direct effects of PAHs and their metabolites could be ignored. At birth, these transgenic mice were normal, but severe skin lesions with itching developed postnatally. The skin lesions were accompanied by inflammation and immunological imbalance and resembled typical atopic dermatitis. We demonstrate that constitutive activation of the AhR pathway causes inflammatory skin lesions and suggests a new mechanism for the exacerbation of inflammatory diseases after exposure to occupational and environmental xenobiotics.
authors.affiliation: Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tauchi
authors.forename: Azumi
authors.initials: A
authors.lastname: Hida
authors.forename: Takaaki
authors.initials: T
authors.lastname: Negishi
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.forename: Shuhei
authors.initials: S
authors.lastname: Noda
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hosoya
authors.forename: Akinori
authors.initials: A
authors.lastname: Yanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007136:Immunoglobulins / Q000097:blood; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D012867:Skin / Q000378:metabolism* / Q000473:pathology
chemical_list: D007136:Immunoglobulins; D018336:Receptors, Aryl Hydrocarbon