Study on the regulatory role of hypoxia sensor or hypoxia-inducible factor 1 system in inflammation

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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. We also demonstrate that lipopolysaccharide induces HIF-1 activation by enhancing both HIF-1a protein expression through a translation-dependent pathway and HIF-1a transcriptional activity in THP-1 cells that have undergone macrophage differentiation, but not in undifferentiated monocytic THP-1 cells, via a pathway that requires the generation of reactive oxygen species.