The interleukin-6 -type cytokine oncostatin M (OSM) acts via the Janus kinase/signal transducer and activator of transcription pathway as well as via activation of mitogen-activated protein kinases and is known to critically regulate processes such as liver development and regeneration, hematopoiesis, and angiogenesis, which are also determined by hypoxia with the hypoxia-inducible factor 1␣ (HIF1␣) as a key component. Here we show that treatment of hepatocytes and hepatoma cells with OSM leads to an increased protein level of HIF1␣ under normoxic and hypoxic conditions. Furthermore, the OSM-dependent HIF1␣ increase is mediated via Janus kinase/signal transducer and activator of transcription 3 and mitogenactivated protein kinase kinase/extracellular signal-regulated kinase 1/2 pathways. OSMmediated HIF1␣ up-regulation did not result from an increase in HIF1␣ protein stability but from increased transcription from the HIF1␣ gene. In addition, we show that the OSM-induced HIF1␣ gene transcription and the resulting enhanced HIF1␣ protein levels are important for the OSM-dependent vascular endothelial growth factor and plasminogen activator inhibitor 1 gene induction associated with several diseases. Conclusion: HIF1␣ levels increase significantly after treatment of hepatocytes and hepatoma cells with OSM, and HIF1␣ contributes to OSM downstream signaling events, pointing to a cross-talk between cytokine and hypoxia signaling in processes such as liver development and regeneration. (HEPATOLOGY 2009;50:253-260.)

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