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.
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.
Cane
Gaëlle
G
INSERM ERI, Nice, France.
Ginouvès
Amandine
A
Marchetti
Sandrine
S
Buscà
Roser
R
Pouysségur
Jacques
J
Berra
Edurne
E
Hofman
Paul
P
Vouret-Craviari
Valérie
V
D018829:Adhesins, Bacterial / Q000378:metabolism; D001422:Bacterial Adhesion; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology*; D004926:Escherichia coli / Q000276:immunology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D053538:Keratin-18 / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D018829:Adhesins, Bacterial; D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D053538:Keratin-18; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A