Hypoxia-inducible factor 1alpha is up-regulated by oncostatin M and participates in oncostatin M signaling.
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 1alpha (HIF1alpha) as a key component. Here we show that treatment of hepatocytes and hepatoma cells with OSM leads to an increased protein level of HIF1alpha under normoxic and hypoxic conditions. Furthermore, the OSM-dependent HIF1alpha increase is mediated via Janus kinase/signal transducer and activator of transcription 3 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 pathways. OSM-mediated HIF1alpha up-regulation did not result from an increase in HIF1alpha protein stability but from increased transcription from the HIF1alpha gene. In addition, we show that the OSM-induced HIF1alpha gene transcription and the resulting enhanced HIF1alpha protein levels are important for the OSM-dependent vascular endothelial growth factor and plasminogen activator inhibitor 1 gene induction associated with several diseases.


CONCLUSIONS
HIF1alpha levels increase significantly after treatment of hepatocytes and hepatoma cells with OSM, and HIF1alpha contributes to OSM downstream signaling events, pointing to a cross-talk between cytokine and hypoxia signaling in processes such as liver development and regeneration.
Vollmer
Stefan
S
Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg.
Kappler
Valérie
V
Kaczor
Jakub
J
Flügel
Daniela
D
Rolvering
Catherine
C
Kato
Nobuyuki
N
Kietzmann
Thomas
T
Behrmann
Iris
I
Haan
Claude
C
D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D053683:Oncostatin M / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053683:Oncostatin M