HIF-1α mediates the induction of IL-8 and VEGF expression on infection with Afa/Dr diffusely adheringE. coliand promotes EMT-like behaviour

Abstract

SummaryMicrobes 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-1a 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-1a protein levels and blocks C1845-induced phosphorylation of the ribosomal S6 protein. Using RNA interference we show that bacteria-induced HIF-1a 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-1a silencing results in reversion of bacteria-induced EMT markers, we speculate that HIF-1a plays a key role linking bacterial infection to angiogenesis, inflammation and some aspects of cancer initiation.

Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype

“…The feasibility of this approach was demonstrated using H 2 O 2 -specific antioxidants, showing they can dramatically reduce SA IL-1␣ expression and ultimately prevent expression of the downstream SASP factors IL-6 and IL-8. Interestingly, IL-8 expression is not sensitive to low O 2 exposure, which is likely explained by the fact that IL-8 expression can be regulated by hypoxia-inducible factor-1␣ (37)(38)(39), which is stabilized in the 0.1-4% O 2 range (40). Although antioxidants limit the expression of IL-1␣, they may also prevent the Ca 2ϩ -dependent processing of this factor.…”

Infection strategies of enteric pathogenic Escherichia coli

“…73 Following target mobilization, enterocyte signaling pathways (e.g., MAPK and PI3K) are activated and IL-8 is synthesized (for the F1845 adhesin this requires HIF-1a 74 ) inducing transepithelial migration of human polymorphonuclear neutrophils (PMN). This stimulates the enterocytes to synthesize TNFa and IL-1β and upregulate DAF to strengthen bacterial adhesion.…”

Epithelial to Mesenchymal Transition in Microbial Pathogenesis

“…We noticed that HIF-1 silencing significantly blocked the expression of Twist1 gene, revealing a role for HIF-1 in the transcriptional regulation of this gene. Furthermore, we observed that C1845-induced HIF-1 protein expression leads to a loss of E-cadherin and cytokeratin 18 and an increase in fibronectin expression, which are reversed in HIF-1 silenced cells (Cane, G., et al, 2010), therefore highlighting the critical role of HIF in DAEC-induced EMT.…”

“…Indeed, inflammatory cytokines, growth factors and bacterial products under normoxic conditions also induce HIFs (Blouin, C. C., et al, 2004, Cane, G., et al, 2010, Peyssonnaux, C., et al, 2008, Zhou, J., et al, 2003. Once activated HIFs, and more particularly HIF-1, controls E-cadherin repression, loss of cell-cell adhesion and cell motility via regulation of the core EMT regulatory factors in various cell types, as described in (Haase, V. H., 2009).…”