hypoxia research::blog

Abstract
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-1a and HIF-1b 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-1a mRNA levels and increased HIF-1a protein synthesis. Differentiation-induced HIF-1a 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-1a protein synthesis. RNA interference studies demonstrated that HIF-1a is dispensable for macrophage differentiation but is required for functional maturation.

Keywords: hypoxia, hypoxia-inducible factor 1, macrophage, differentiation, translation, RNA interference