Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions
Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions
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DOI：
10.1128/mcb.25.21.9360-9368.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
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作者：
Tauchi, M;Hida, A;Yamamoto, M
多环芳烃（PAHs）的职业和环境暴露已被认为会引起炎症和/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。先前的研究暗示多环芳烃作为刺激物和过敏原的参与，从氧化的多环芳烃产生的活性氧被认为是一个加剧因素。多环芳烃也可能通过激活芳香烃受体（AhR）介导的转录而参与发病，因为多环芳烃是AhR的有效诱导剂。为了解决这一点，我们产生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系。在这些小鼠品系中，AhR活性在没有配体的情况下组成性增强，因此可以忽略多环芳烃及其代谢物的任何其他直接影响。出生时，这些转基因小鼠是正常的，但出生后出现严重的皮肤损伤和瘙痒。皮损伴有炎症和免疫失衡，类似典型的特应性皮炎。我们证明，组成性激活的AhR途径导致炎症性皮肤病变，并提出了一个新的机制，暴露于职业和环境外源性物质后，炎症性疾病的恶化。
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.