IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis

FASEB J. 2003 Nov;17(14):2115-7. doi: 10.1096/fj.03-0329fje. Epub 2003 Sep 4.


Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.

MeSH terms

  • Cell Line, Tumor
  • Cyclooxygenase 2
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation / complications
  • Interleukin-1 / pharmacology*
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • NF-kappa B / metabolism*
  • Neoplasms / etiology
  • Neoplasms / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Signal Transduction
  • Transcription Factors / biosynthesis*
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin-Protein Ligases / physiology
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Von Hippel-Lindau Tumor Suppressor Protein


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Phosphatidylinositol 3-Kinases
  • VHL protein, human