HIF-1alpha mediates the induction of IL-8 and VEGF expression on infection with Afa/Dr diffusely adhering E. coli and promotes EMT-like behaviour

Cell Microbiol. 2010 May 1;12(5):640-53. doi: 10.1111/j.1462-5822.2009.01422.x. Epub 2009 Dec 21.


Microbes regulate a large panel of intracellular signalling events that can promote inflammation and/or enhance tumour progression. Indeed, it has been shown that infection of human intestinal cells with the Afa/Dr diffusely adhering E. coli C1845 strain induces expression of pro-angiogenic and pro-inflammatory genes. Here, we demonstrate that exposure of cryptic-like intestinal epithelial cells to C1845 bacteria induces HIF-1alpha protein levels. This effect depends on the binding of F1845 adhesin to the membrane-associated DAF receptor that initiates signalling cascades promoting translational mechanisms. Indeed, inhibition of MAPK and PI-3K decreases HIF-1alpha protein levels and blocks C1845-induced phosphorylation of the ribosomal S6 protein. Using RNA interference we show that bacteria-induced HIF-1alpha regulates the expression of IL-8, VEGF and Twist1, thereby pointing to a role for HIF-1 in angiogenesis and inflammation. In addition, infection correlates with a loss of E-cadherin and cytokeratin 18 and a rise in fibronectin, suggesting that bacteria may induce an epithelial to mesenchymal transition-like phenotype. Since HIF-1alpha silencing results in reversion of bacteria-induced EMT markers, we speculate that HIF-1alpha plays a key role linking bacterial infection to angiogenesis, inflammation and some aspects of cancer initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adhesins, Bacterial / metabolism
  • Bacterial Adhesion
  • Cadherins / metabolism
  • Cell Line
  • Epithelial Cells / microbiology*
  • Escherichia coli / immunology*
  • Gene Expression Regulation*
  • Gene Silencing
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Interleukin-8 / biosynthesis*
  • Keratin-18 / metabolism
  • Nuclear Proteins / biosynthesis
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Twist-Related Protein 1 / biosynthesis
  • Vascular Endothelial Growth Factor A / biosynthesis*


  • Adhesins, Bacterial
  • Cadherins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-8
  • Keratin-18
  • Nuclear Proteins
  • RNA, Small Interfering
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A