Oncostatin M upregulates HIF-1 alpha in breast tumor associated macrophages independent of intracellular oxygen concentration

Aims: HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1-alpha is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-alpha levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-alpha upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration. Main methods: THP-1 derived macrophages were treated with OSM. HIF1-alpha levels and interaction with pVHL were evaluated via immunoblot-analysis and Co-immunoprecipitation. Translocation of HIF1-alpha to nucleus was visualized using confocal-microscopy. Fold change in mRNA levels of ARG-1 and COX-2 was analyzed using RT-PCR. Key findings: Current study demonstrates that OSM treatment to TAMs led to an increased expression of HIF1-alpha under normoxic conditions via activation of mTORC2. This HIF1-alpha upregulation was dependent on both de novo synthesis of HIF1-alpha and its enhanced stability due to disruption of its binding to pVHL. Furthermore, we evaluated that OSM not only enhances the expression of HIF1-alpha but also increases its localization to nucleus where it acts as a transcription factor regulating expression of genes like ARG-1 and COX-2.