Cheng J, Turksen K, Yu Q C, Schreiber H, Teng M, Fuchs E
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, University of Chicago, Illinois 60637.
Genes Dev. 1992 Aug;6(8):1444-56. doi: 10.1101/gad.6.8.1444.
Tumor necrosis factor alpha (TNF alpha) orchestrates a wide range of effects that combat severe infections in animals. At lower levels, TNF alpha plays an important protective role in stimulating chemotaxis and antimicrobial activity of neutrophils, macrophages, and eosinophils. During chronic illness, TNF alpha secretion can be elevated markedly, giving rise to cachexia, hemorrhage, necrosis and, ultimately, death. Although TNF alpha may mediate many of its effects through macrophages, 30% of TNF alpha injected into animals concentrates in the skin. In recent years, it has been shown that keratinocytes can be induced to synthesize TNF alpha. To explore the role of TNF alpha synthesis in keratinocytes, we used a keratin-14 (K14) promoter to target human TNF alpha expression in the epidermis and other stratified squamous epithelia of transgenic mice. Most mice expressing the K14-TNF alpha transgene stopped gaining weight within 1 week postbirth, and exhibited retarded hair growth. In the skin, adipose production was profoundly inhibited, whereas signs of fibrosis and immune infiltration were evident in the dermis. Over time, the epidermis exhibited an increased stratum corneum, as signs of necrosis began to appear in the skin. Within 3-5 weeks, the mice displayed features characteristic of cachexia and necrosis. Our results suggest that TNF alpha expression by keratinocytes not only plays a role in inflammatory and graft-versus-host-disease-like responses in the skin, but also in other tissues, apparently by virtue of stratified squamous epithelial-derived TNF alpha entering the bloodstream. Our results have enabled the first evaluation of many of the effects of TNF alpha in transgenic animals.
肿瘤坏死因子α（TNFα）在动物体内协调发挥多种对抗严重感染的作用。在较低水平时，TNFα在刺激中性粒细胞、巨噬细胞和嗜酸性粒细胞的趋化性及抗菌活性方面发挥重要的保护作用。在慢性病期间，TNFα的分泌可显著升高，导致恶病质、出血、坏死，最终导致死亡。尽管TNFα可能通过巨噬细胞介导其许多效应，但注入动物体内的TNFα有30%集中在皮肤中。近年来，已证明角质形成细胞可被诱导合成TNFα。为了探究角质形成细胞中TNFα合成的作用，我们使用角蛋白14（K14）启动子在转基因小鼠的表皮和其他复层鳞状上皮中靶向表达人TNFα。大多数表达K14-TNFα转基因的小鼠在出生后1周内停止体重增加，并表现出毛发生长迟缓。在皮肤中，脂肪生成受到严重抑制，而真皮中纤维化和免疫浸润的迹象明显。随着时间的推移，表皮角质层增厚，皮肤开始出现坏死迹象。在3 - 5周内，小鼠表现出恶病质和坏死的特征。我们的结果表明，角质形成细胞表达的TNFα不仅在皮肤的炎症和移植物抗宿主病样反应中起作用，在其他组织中也起作用，显然是由于复层鳞状上皮来源的TNFα进入血液循环。我们的结果首次对TNFα在转基因动物中的许多效应进行了评估。
