Oncostatin M, a Cytokine Released by Activated Mononuclear Cells, Induces Epithelial Cell-Myofibroblast Transdifferentiation via Jak/Stat Pathway Activation

Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithe- lial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofi- broblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for-smooth muscle actin, collagen I, and fibronectin EDA (markers for the myofibro- blastic phenotype) were increased, whereas those for E-cad- herin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to iden- tify 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 consec- utive 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 ex- pression of the oncostatin M (OSM)-specific receptor sub- unit 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 -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. Tubulointerstitial fibrosis is the principal hallmark of most types of progressive renal disease. Initial renal injury stimu- lates various types of kidney cells to produce inflammatory mediators. These mediators activate renal tubule epithelial cells and peritubular capillary endothelial cells and facilitate infiltration of mononuclear cells into the interstitium. Histo- logically, progressive renal disease is characterized by an in- terstitial infiltrate of mononuclear cells. The interactions be- tween inflammatory infiltrates and resident tubular cells contribute to ongoing inflammation, formation and activation of myofibroblasts, and ultimately interstitial fibrosis. The piv- otal role of inflammatory infiltration in the progression of tubulointerstitial fibrosis is supported by the strict correlation between tubular atrophy, interstitial fibrosis, and the extent of interstitial infiltration (1,2).