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.) O ncostatin M (OSM) is an interleukin (IL)-6type cytokine produced by monocytes and macrophages, T cells, and several other cell types. OSM receptors are widely expressed and are composed of the common signal transducer gp130 in complex with the LIFR or the OSMR. OSM has pleiotropic effects that in part overlap with those of other IL-6 -type cytokines; examples include inflammation, neurogenesis, regulation of cell proliferation, and fibrosis. [1][2][3] In addition, OSM plays a crucial role in the orchestration of hematopoiesis and liver development. 3 Upon OSM-induced receptor clustering, Janus kinases-mainly Janus kinase 1-are activated, phosphorylate tyrosines within the receptor that recruit other signaling proteins with matching SH2 domains such as signal transducers and activators of transcription (STATs) or adapter proteins for the mitogen-activated protein kinases to the receptor. The major signaling cascades activated by OSM include STAT3 as well as the extracellular signal-regulated kinase (Erk) 1/2 and p38 pathways. [2][3][4] Several processes such as hematopoiesis, angiogenesis, liver development, metabolism, inflammation, and tu-