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

Joanna Nightingale^*, Sharmila Patel^*, Naotaka Suzuki^*, Roger Buxton, Ken-ichro Takagi^*, Jun Suzuki, Yoshihiko Sumi, Atsushi Imaizumi, Roger M. Mason and Zhi Zhang^*

*Teijin Biomedical Laboratory, Medical Research Council Technology, London, UK; Division of Mycobacterial Research, National Institute for Medical Research, London, UK; Institute for Bio-Medical Research, Teijin Ltd., Tokyo, Japan; and Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London, UK.

Correspondence to Dr. Zhi Zhang, Teijin Biomedical Laboratory, Medical Research Council Technology, 1-3 Burtonhole Lane, London NW7 1AD, UK. Phone: 44-20-8906-7177; Fax: 44-20-8906-7200;

ABSTRACT. 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 -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 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 -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. E-mail: zzhang@tech.mrc.ac.uk

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