Activation of hypoxia-inducible factor 1 during macrophage differentiation.
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-1alpha and HIF-1beta 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-1alpha mRNA levels and increased HIF-1alpha protein synthesis. Differentiation-induced HIF-1alpha 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-1alpha protein synthesis. RNA interference studies demonstrated that HIF-1alpha is dispensable for macrophage differentiation but is required for functional maturation.
The Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
Tomoyuki
T
Oda
Kiichi
K
Hirota
Kenichiro
K
Nishi
Satoshi
S
Takabuchi
Seiko
S
Oda
Hiroko
H
Yamada
Toshiyuki
T
Arai
Kazuhiko
K
Fukuda
Toru
T
Kita
Takehiko
T
Adachi
Gregg L
GL
Semenza
Ryuji
R
Nohara
D017398:Alternative Splicing / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger