Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation
Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation
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DOI：
10.1097/01.asn.0000102479.92582.43
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发表时间：
2004-01-01
影响因子：
13.6
通讯作者：
Zhang, Z
中科院分区：
文献类型：
--
作者：
Nightingale, J;Patel, S;Zhang, Z
炎症浸润和肾小管上皮细胞之间的相互作用可能通过促进上皮细胞-肌成纤维细胞转分化（EMT）在肾小管间质纤维化的发展中发挥重要作用。用活化的PBMC条件培养基处理后，人近端肾小管上皮细胞转分化为肌成纤维细胞。α-平滑肌肌动蛋白、胶原蛋白I和纤连蛋白EDA（+）（肌纤维母细胞表型的标志物）的mRNA和蛋白水平升高，而E-钙粘蛋白和细胞角蛋白19（上皮表型的标志物）的mRNA和蛋白水平降低。cDNA微阵列分析用于识别基因表达的其他变化，这些变化可能指向驱动EMT的新分子机制。在1176个阵列基因中，61个在检查的5个时间点（0.5、4、8、16和48 h）中的至少两个连续时间点表现出至少两倍的变化。在这些基因中，59%上调，41%下调。该阵列表明，肾上皮细胞暴露于活化的PBMC条件培养基（其中含有高水平的OSM）后4至48小时，抑瘤素M（OSM）特异性受体β亚基的表达上调。在另外的实验中，证明了OSM诱导EMT。OSM激活上皮细胞中的Jak/Stat信号通路，并且Jak 2的特异性抑制剂在暴露于OSM后阻断其磷酸化以及α-肌动蛋白的诱导和细胞角蛋白19表达的丧失。因此，OSM是一种新的EMT诱导剂，可能是炎症浸润产生的几种细胞因子之一，有助于这种和随后的肾小管间质纤维化。
Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for alpha-smooth muscle actin, collagen I, and fibronectin EDA(+) (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to identify other changes in gene expression that might point to novel molecular mechanisms driving EMT. Of 1176 array genes, 61 demonstrated at least a twofold change at at least two consecutive time points, of the five time points examined (0.5, 4, 8, 16, and 48 h). Of these genes, 59% were upregulated and 41% were downregulated. The array indicated upregulation of expression of the oncostatin M (OSM)-specific receptor beta subunit from 4 to 48 h after exposure of kidney epithelial cells to activated PBMC conditioned medium, which contained high levels of OSM. In additional experiments, it was demonstrated that OSM induced EMT. OSM activated the Jak/Stat signaling pathway in epithelial cells, and a specific inhibitor of Jak2 blocked both its phosphorylation after exposure to OSM and the induction of alpha-actin and loss of cytokeratin 19 expression. Therefore, OSM is a novel inducer of EMT and is likely to be one of several cytokines produced by inflammatory infiltrates that contribute to this and subsequent tubulointerstitial fibrosis.