Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts.
Rheumatoid arthritis and periodontitis are inflammatory diseases modulated by proinflammatory cytokines [e.g. interleukin (IL-1) 1 and tumour necrosis factor alpha], which activate local fibroblasts to do the following: (1) proliferate, (2) induce gene expression and (3) produce destructive metalloproteinases. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor (composed of HIF-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear transporter) that is modulated by hypoxia. HIF-1 binds to and induces several genes containing an HIF-1 consensus-binding site, including vascular endothelial growth factor and several glycolytic enzymes. Through differential screening of a human synovial fibroblast cDNA library, we identified HIF-1alpha as a clone up-regulated by IL-1. The mRNA for HIF-1alpha subunit was increased 3-4-fold by Northern blot analysis after cells had been incubated for 3 h in the presence of IL-1. In addition, IL-1 increased the binding of the heterodimer HIF-1 to the HIF consensus sequence. These results suggest that HIF-1 might have a role in inflammation, possibly in attempting to re-establish homoeostasis.
Thornton
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RD
Philadelphia College of Osteopathic Medicine, Department of Biochemistry/Molecular Biology, 4170 City Avenue, Philadelphia, PA 19131, USA. rutht@pcom.edu
Lane
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Borghaei
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Pease
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Caro
J
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Mochan
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D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha