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1 The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Osaka, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
2 The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Osaka, Japan; Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, Kyoto, Japan
3 The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Osaka, Japan; Department of Anesthesiology, Kansai Medical University, Moriguchi-City, Osaka, Japan
4 Department of Hematology and Oncology, Kyoto University Hospital, Kyoto University, Kyoto, Kyoto, Japan
5 Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, Kyoto, Japan
6 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
7 The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Osaka, Japan
8 Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: hif1{at}mac.com.
Monocytes/macrophages of the myeloid lineage are the main cellular effectors of innate immunity. Hypoxia inducible factor-1 (HIF-1) is essential for myeloid cell activation in response to inflammatory stimuli. However, it has not been established whether HIF-1 activity is induced during differentiation from monocyte to macrophage. We demonstrate that macrophage differentiation of THP-1 cells or monocytes from peripheral blood induces increased expression of both HIF-1
and HIF-1
as well as increased HIF-1 transcriptional activity leading to increased expression of HIF-1 target genes. The increased HIF-1 activity in differentiated THP-1 cells resulted from the combined effect of increased HIF-1 mRNA levels and increased HIF-1 protein synthesis. Differentiation-induced HIF-1 protein and mRNA and HIF-1-dependent gene expression was blocked by treating cells with an inhibitor of the protein kinase C or MAP kinase signaling pathway. THP-1 cell differentiation was also associated with increased phosphorylation of the translational regulatory proteins p70 S6 kinase, S6 ribosomal protein, eukaryotic initiation factor 4E, and 4E binding protein 1, thus providing a possible mechanism for the modulation of HIF-1 protein synthesis. RNA interference studies demonstrated that HIF-1 is dispensable for macrophage differentiation but is required for functional maturation.
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