Kirkley Kelly S, Walton Kelly D, Duncan Colleen, Tjalkens Ronald B
Departments of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado.
Departments of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado.
Comp Med. 2017 Oct 1;67(5):407-415.
The deletion of NFκB in epithelial tissues by using skin-specific promoters can cause both tumor formation and severe inflammatory dermatitis, indicating that this signaling pathway is important for the maintenance of immune homeostasis in epithelial tissues. In the present study, we crossed mice transgenic for loxP-Ikbk2 and human Gfap-cre to selectively delete IKK2 in CNS astrocytes. Unexpectedly, a subset of mice developed severe and progressive skin lesions marked by hyperplasia, hyperkeratosis, dysplasia, inflammation, and neoplasia with a subset of lesions diagnosed as squamous cell carcinoma (SCC). The development of lesions was monitored over a 3.5-y period and over 4 filial generations. Average age of onset of was 4 mo of age with 19.5% of mice affected with frequency increasing in progressive generations. Lesion development appeared to correlate not only with unintended IKK2 deletion in GFAP expressing cells of the epidermis, but also with increased expression of TNF in lesioned skin. The skins changes described in these animals are similar to those in transgenic mice with an epidermis-specific deletion of NFκB and thus represents another genetic mouse model that can be used to study the role of NFκB signaling in regulating the development of SCC.
利用皮肤特异性启动子在上皮组织中删除NFκB可导致肿瘤形成和严重的炎症性皮肤病，这表明该信号通路对于维持上皮组织中的免疫稳态很重要。在本研究中，我们将loxP-Ikbk2转基因小鼠与人类Gfap-cre小鼠杂交，以选择性删除中枢神经系统星形胶质细胞中的IKK2。出乎意料的是，一部分小鼠出现了严重且进行性的皮肤病变，其特征为增生、角化过度、发育异常、炎症和肿瘤形成，其中一部分病变被诊断为鳞状细胞癌（SCC）。在3.5年的时间里对4个连续子代的病变发展进行了监测。平均发病年龄为4个月龄，19.5%的小鼠受到影响，且在连续几代中发病率增加。病变发展似乎不仅与表皮中表达GFAP的细胞中意外删除IKK2有关，还与病变皮肤中TNF表达增加有关。这些动物中描述的皮肤变化与表皮特异性删除NFκB的转基因小鼠中的变化相似，因此代表了另一种可用于研究NFκB信号在调节SCC发展中作用的基因小鼠模型。
