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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Activation of hypoxia-inducible factor 1 during macrophage differentiation

¹The Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka; ²Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto; ³Department of Anesthesia, Kyoto University Hospital, Kyoto; ⁴Department of Anesthesiology, Kansai Medical University, Osaka; ⁵Department of Hematology and Oncology, Kyoto University Hospital, Kyoto University, Kyoto, Japan; and ⁶Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 12 December 2005 ; accepted in final form 7 February 2006

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.

translation; RNA interference

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