Yamamoto K, Loskutoff D J
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Lab Invest. 2000 Oct;80(10):1561-70. doi: 10.1038/labinvest.3780166.
Although elevated levels of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in renal disease, the tissue distribution and cellular localization of the induced cytokines is not well established. In this study, we investigated the expression of these cytokines during the progression of lupus nephritis in MRL lpr/lpr mice. The concentration of both cytokines increased in the plasma of these animals in an age-dependent manner, and there was an age-dependent induction of TGF-beta and TNF-alpha mRNAs in their kidneys. Although the increase in TGF-beta mRNA was specific for the kidney, the increase in TNF-alpha mRNA was widespread and also could be demonstrated in the liver, lung, and heart. In situ hybridization analysis of renal tissues from the lupus-prone mice localized TGF-beta mRNA to the glomerulus, and more specifically, to resident glomerular cells and inflammatory cells infiltrating periglomerular spaces in the nephritic lesions. The signals for TNF-alpha mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAI-1) is known to be elevated in the glomeruli of MRL lpr/lpr mice, and intraperitoneal administration of either TGF-beta or TNF-alpha into normal mice markedly induced the expression of this potent inhibitor of fibrinolysis in renal glomerular or tubular cells in vivo. These results suggest that the increased renal expression of both cytokines may contribute to the development of lupus nephritis in this model and raise the possibility that PAI-1 may be involved. The fact that TGF-beta is specifically induced in the kidney whereas TNF-alpha increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-beta.
尽管转化生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α）水平升高与肾脏疾病有关，但诱导细胞因子的组织分布和细胞定位尚未完全明确。在本研究中，我们调查了这些细胞因子在MRL lpr/lpr小鼠狼疮性肾炎进展过程中的表达情况。这两种细胞因子在这些动物血浆中的浓度均呈年龄依赖性增加，并且其肾脏中TGF-β和TNF-α mRNA也呈年龄依赖性诱导。虽然TGF-β mRNA的增加在肾脏中具有特异性，但TNF-α mRNA的增加较为广泛，在肝脏、肺和心脏中也可检测到。对狼疮易感小鼠肾脏组织进行原位杂交分析发现，TGF-β mRNA定位于肾小球，更具体地说，定位于驻留的肾小球细胞和浸润在肾炎病变肾小球周围间隙的炎性细胞。TNF-α mRNA信号仅在炎性细胞中检测到，并分布于整个患肾炎的肾脏。已知纤溶酶原激活物抑制剂-1（PAI-1）在MRL lpr/lpr小鼠的肾小球中升高，向正常小鼠腹腔注射TGF-β或TNF-α均可在体内显著诱导肾小球或肾小管细胞中这种强效纤维蛋白溶解抑制剂的表达。这些结果表明，这两种细胞因子在肾脏中的表达增加可能促成了该模型中狼疮性肾炎的发展，并增加了PAI-1可能参与其中的可能性。TGF-β在肾脏中特异性诱导而TNF-α在多种组织中增加这一事实，支持了该疾病的肾脏特异性反映TGF-β异常表达的假说。
