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Molecular and Cellular Biology, November 2005, p. 9360-9368, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9360-9368.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Constitutive Expression of Aryl Hydrocarbon Receptor in Keratinocytes Causes Inflammatory Skin Lesions

Masafumi Tauchi,1,2 Azumi Hida,1,2 Takaaki Negishi,3 Fumiki Katsuoka,1,2 Shuhei Noda,1,2 Junsei Mimura,1,2,6 Tomonori Hosoya,4 Akinori Yanaka,1 Hiroyuki Aburatani,5 Yoshiaki Fujii-Kuriyama,2,6 Hozumi Motohashi,1,2* and Masayuki Yamamoto1,2,4

Graduate School of Comprehensive Human Sciences,1 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577,2 Mochida Pharmaceutical Co., Ltd., Pharmaceutical Research Center, 722 Uenohara, Jimba, Gotemba 412-8524,3 ERATO Environmental Response Project, Japan Science and Technology Corporation, 1-1-1 Tennoudai, Tsukuba 305-8577,4 Research Center for Advance Science and Technology, The University of Tokyo, Tokyo 153-8904,5 SORST, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan6

Received 23 May 2005/ Returned for modification 25 June 2005/ Accepted 7 August 2005

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.

* Corresponding author. Mailing address: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan. Phone: 81-29-853-7320. Fax: 81-29-853-7318. E-mail: hozumim{at}tara.tsukuba.ac.jp.

Molecular and Cellular Biology, November 2005, p. 9360-9368, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9360-9368.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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