Activation of hypoxia-inducible factor 1 during macrophage differentiation

Tomoyuki Oda, Kiichi Hirota, Kenichiro Nishi, Satoshi Takabuchi, Seiko Oda, Hiroko Yamada, Toshiyuki Arai, Kazuhiko Fukuda, Toru Kita, Takehiko Adachi, Gregg L. Semenza, Ryuji Nohara

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)C104-C113
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1
StatePublished - 2006


  • RNA interference
  • Translation

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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