Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions.
Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex that has been recognized primarily for its role in the maintenance of oxygen and energy homoeostasis. The HIF-1alpha subunit is O(2) labile and is degraded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. The present review summarizes evidence that HIF-1 is also involved in immune reactions. Immunomodulatory peptides, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), stimulate HIF-1 dependent gene expression even in normoxic cells. Both the hypoxic and the cytokine-induced activation of HIF-1 involve the phosphatidylinositol- 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways. In addition, heat shock proteins (HSP) and other cofactors interact with HIF-1 subunits. HIF-1 increases the transcription of several genes for proteins that promote blood flow and inflammation, including vascular endothelial growth factor (VEGF), heme oxygenase-1, endothelial and inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2). The pharmacologic activation of the HIF-1 complex can be desirable in ischemic and inflammatory disorders. In contrast, HIF-1 blockade may be beneficial to prevent tumor angiogenesis and tumor growth.
Hellwig-Bürgel
Thomas
T
Institute of Physiology, University of Luebeck, D-23538 Luebeck, Germany.
Stiehl
Daniel P
DP
Wagner
Anika E
AE
Metzen
Eric
E
Jelkmann
Wolfgang
W
D000818:Animals; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020935:MAP Kinase Signaling System / Q000276:immunology; D009687:Nuclear Proteins / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology*
D016207:Cytokines; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex