Rüger B M, Hasan Q, Erb K J, Davis P F
Renal Research Unit, Department of Medicine, Wellington School of Medicine, Wellington, New Zealand.
Int J Exp Pathol. 1999 Jun;80(3):113-23. doi: 10.1046/j.1365-2613.1999.00105.x.
Recent reports have suggested the involvement of interleukin-4 (IL-4) in glomerular pathophysiology. Using immunohistochemistry and reverse transcriptase polymerase chain reaction we investigated the renal lesions in transgenic (tg) mice with widely distributed IL-4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor-beta (TGF-beta) and IL-4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesangial sclerosis leading to renal failure. Renal IL-4 transcript expression, mesangial accumulation of collagen types I, III, IV and V, and immune deposition accompanied by increased expression of TGF-beta1 protein and mRNA were observed. Seven day-old transgenic animals showed early renal fibrotic changes in the absence of immune deposits or TGF-beta1 upregulation. The sera of transgenic mice not only showed elevated levels of circulating IL-4 (tg: 76.6 pg/ml +/- 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decreased TGF-beta1 levels (tg: 18.9 ng/ml +/- 4.1 vs wt: 38.7 ng/ml +/- 2.9; P < 0.005). The disease severity correlated with the serum IL-4/TGF-beta1 ratio rather than with the IL-4 concentration. These data suggest that renal IL-4 production results in matrix accumulation prior to any immunological insult, that increased circulating IL-4/TGF-beta1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF-beta1 expression following glomerular Ig deposition accelerates the sclerosis and exacerbates disease development.
最近的报告表明白细胞介素-4（IL-4）参与肾小球病理生理学过程。我们利用免疫组织化学和逆转录聚合酶链反应，研究了白细胞介素-4广泛表达（包括在肾脏中表达）的转基因（tg）小鼠的肾脏病变，并通过酶联免疫吸附测定法测量了细胞因子转化生长因子-β（TGF-β）和IL-4的血清水平。转基因动物表现出肾小球肥大，并伴有进行性系膜硬化，最终导致肾衰竭。观察到肾脏中IL-4转录本表达、I型、III型、IV型和V型胶原在系膜中的积聚以及免疫沉积，同时伴有TGF-β1蛋白和mRNA表达增加。7日龄的转基因动物在没有免疫沉积物或TGF-β1上调的情况下就出现了早期肾脏纤维化变化。转基因小鼠的血清不仅显示循环IL-4水平升高（tg：76.6 pg/ml±7.1，野生型（wt）：<3 pg/ml），而且TGF-β1水平显著降低（tg：18.9 ng/ml±4.1，wt：38.7 ng/ml±2.9；P<0.005）。疾病严重程度与血清IL-4/TGF-β1比值相关，而非与IL-4浓度相关。这些数据表明，在任何免疫损伤之前，肾脏产生的IL-4会导致基质积聚，循环中IL-4/TGF-β1比值升高与肾脏免疫病理表现相关，并且肾小球Ig沉积后肾脏TGF-β1表达上调会加速硬化并加剧疾病发展。
