| Project/Area Number |
16591576
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Kyoto University (2005)
Tazuke Kofukai Medical Research Institute (2004) |
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Principal Investigator |
HIROTA Kiichi Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (00283606)
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| Co-Investigator(Kenkyū-buntansha) |
服部 登 財団法人田附興風会, 医学研究所・第5研究部, 主任研究員 (00283169)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | hypoxia / macrophage / differentiation / hypoxia sensor / inflammation / HIF-1 |
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| Research 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. 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.
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