Lee M S, Gu D, Feng L, Curriden S, Arnush M, Krahl T, Gurushanthaiah D, Wilson C, Loskutoff D L, Fox H
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Am J Pathol. 1995 Jul;147(1):42-52.
Transgenic mice expressing transforming growth factor-beta 1 (TGF-beta 1) in the pancreatic beta-islet cells directed by human insulin promoter were produced to study in vivo effects of TGF-beta 1. Fibroblast proliferation and abnormal deposition of extracellular matrix were observed from birth onward, finally replacing almost all the exocrine pancreas. Cellular infiltrates comprising macrophages and neutrophils were also observed. Plasminogen activator inhibitor was induced in the transgenic pancreas as well as fibronectin and laminin, partly explaining accumulation of extracellular matrix. TGF-beta 1 inhibited proliferation of acinar cells in vivo as evidenced by decreased bromodeoxyuridine incorporation. Development of pancreatic islets was dysregulated, resulting in small islet cell clusters without formation of normal adult islets; however, the overall islet cell mass was not significantly diminished. Additional transgenic lines with less pronounced phenotypes had less expression of TGF-beta 1 transgene. These findings suggest that TGF-beta 1 might be a mediator of diseases associated with extracellular matrix deposition such as chronic pancreatitis, and this mouse model will be useful for further analysis of the in vivo effects of TGF-beta 1, including its potential for immunosuppression.
为了研究转化生长因子β1（TGF-β1）的体内效应，制备了在人胰岛素启动子指导下于胰腺β胰岛细胞中表达TGF-β1的转基因小鼠。从出生起就观察到成纤维细胞增殖和细胞外基质的异常沉积，最终几乎取代了所有外分泌胰腺。还观察到由巨噬细胞和中性粒细胞组成的细胞浸润。转基因胰腺中诱导了纤溶酶原激活物抑制剂以及纤连蛋白和层粘连蛋白，这部分解释了细胞外基质的积累。TGF-β1在体内抑制腺泡细胞增殖，溴脱氧尿苷掺入减少证明了这一点。胰岛的发育失调，导致形成小的胰岛细胞簇，未形成正常的成年胰岛；然而，总的胰岛细胞量并未显著减少。具有不太明显表型的其他转基因系中TGF-β1转基因的表达较少。这些发现表明，TGF-β1可能是与细胞外基质沉积相关疾病（如慢性胰腺炎）的介质，并且该小鼠模型将有助于进一步分析TGF-β1的体内效应，包括其免疫抑制潜力。
