Tauchi Masafumi, Hida Azumi, Negishi Takaaki, Katsuoka Fumiki, Noda Shuhei, Mimura Junsei, Hosoya Tomonori, Yanaka Akinori, Aburatani Hiroyuki, Fujii-Kuriyama Yoshiaki, Motohashi Hozumi, Yamamoto Masayuki
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.
Mol Cell Biol. 2005 Nov;25(21):9360-8. doi: 10.1128/MCB.25.21.9360-9368.2005.
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.
职业性和环境性接触多环芳烃（PAHs）已被认为会引发炎症和/或过敏性疾病，包括哮喘、鼻炎和皮炎。这种PAH介导的炎症的分子机制仍有待阐明。先前的研究表明PAHs作为刺激物和过敏原参与其中，含氧PAHs产生的活性氧被认为是一个加重因素。PAHs也有可能通过激活芳烃受体（AhR）介导的转录来促进发病机制，因为PAHs是AhR的有效诱导剂。为了解决这一问题，我们构建了在角质形成细胞中表达AhR组成型活性形式的转基因小鼠品系。在这些小鼠品系中，在没有配体的情况下AhR活性被组成型增强，这样PAHs及其代谢产物的任何其他直接影响都可以被忽略。出生时，这些转基因小鼠是正常的，但出生后会出现伴有瘙痒的严重皮肤病变。皮肤病变伴有炎症和免疫失衡，类似于典型的特应性皮炎。我们证明AhR途径的组成型激活会导致炎症性皮肤病变，并提示了接触职业性和环境性外源性物质后炎症性疾病加重的一种新机制。
