Pawluczyk I Z, Harris K P
Department of Nephrology, Leicester General Hospital, England, United Kingdom.
Kidney Int. 1998 Jul;54(1):62-70. doi: 10.1046/j.1523-1755.1998.00XXX.x.
The development of glomerulosclerosis has been associated with the presence of the cytokines transforming growth factor-beta 1 (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-1 beta (IL-1 beta), at some stage in the glomerulus. To better understand the role of these cytokines in the scarring process their effect on rat mesangial cell fibronectin production was investigated.
Mesangial cells were exposed to 10 ng/ml of either TGF-beta 1, TNF-alpha, or IL-1 beta or to TGF-beta 1 in combination with TNF-alpha or IL-1 beta. Tissue culture supernatants and cell lysates were assayed for fibronectin. Supernatants were also assayed for TGF-beta 1. Northern blot analyses probing for fibronectin, transin, TIMP-1 and TGF-beta 1 were carried out on RNA extracted from mesangial cells exposed to individual and combinations of cytokines.
Individually these cytokines were only able to induce modest increases in fibronectin protein levels. However, when mesangial cells were exposed to TGF-beta 1 in combination with either TNF-alpha or IL-1 beta then fibronectin levels were synergistically up-regulated approximately fivefold over unstimulated levels. Northern analysis demonstrated that fibronectin mRNA levels in the combination were also synergistically increased. In contrast, rat transin gene expression in the combinations was reduced to well below levels induced by TNF-alpha and IL-1 beta individually. In addition, synergistic up-regulation of both TGF-beta 1 protein and message by the cytokine combinations was also observed. TGF-beta 1: TNF-alpha and TGF-beta 1: IL-1 beta induced additive increases in TIMP-1 (tissue inhibitor of metalloproteinases-1) mRNA levels.
These data illustrate that complex interactions can occur between cytokines within the glomerulus modulating both matrix synthetic and degradation pathways. These could initiate the scarring process and the development of glomerulosclerosis.
肾小球硬化的发展与细胞因子转化生长因子-β1（TGF-β1）、肿瘤坏死因子-α（TNF-α）和/或白细胞介素-1β（IL-1β）在肾小球某些阶段的存在有关。为了更好地理解这些细胞因子在瘢痕形成过程中的作用，研究了它们对大鼠系膜细胞纤连蛋白产生的影响。
将系膜细胞暴露于10 ng/ml的TGF-β1、TNF-α或IL-1β，或TGF-β1与TNF-α或IL-1β的组合中。检测组织培养上清液和细胞裂解物中的纤连蛋白。还检测上清液中的TGF-β1。对暴露于单个细胞因子及其组合的系膜细胞提取的RNA进行Northern印迹分析，检测纤连蛋白、转胶酶、金属蛋白酶组织抑制因子-1（TIMP-1）和TGF-β1。
单独使用这些细胞因子仅能使纤连蛋白蛋白水平有适度增加。然而，当系膜细胞暴露于TGF-β1与TNF-α或IL-1β的组合时，纤连蛋白水平比未刺激水平协同上调约五倍。Northern分析表明，组合中的纤连蛋白mRNA水平也协同增加。相反，组合中大鼠转胶酶基因表达降至远低于单独TNF-α和IL-1β诱导的水平。此外，还观察到细胞因子组合对TGF-β1蛋白和信使核糖核酸的协同上调。TGF-β1：TNF-α和TGF-β1：IL-1β诱导TIMP-1 mRNA水平的累加增加。
这些数据表明，肾小球内细胞因子之间可发生复杂相互作用，调节基质合成和降解途径。这些相互作用可能启动瘢痕形成过程及肾小球硬化的发展。
