ExoU Activates NF-[kappa]B and Increases IL-8/KC Secretion during Pseudomonas aeruginosa Infection

ExoU, a Pseudomonas aeruginosa cytotoxin injected into host cytosol by type III secretion system, exhibits a potent proinflammatory activity that leads to a marked recruitment of neutrophils to infected tissues. To evaluate the mechanisms that account for neutrophil infiltration, we investigated the...

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Bibliographic Details
Published inPloS one Vol. 7; no. 7; p. e41772
Main Authors de Lima, Carolina Diettrich Mallet, Calegari-Silva, Teresa Cristina, Pereira, Renata Meirelles Santos, Santos, Sabrina Alves de Oliveira Lima, Lopes, Ulisses Gazos, Plotkowski, Maria-Cristina Maciel, Saliba, Alessandra Mattos
Format Journal Article
LanguageEnglish
Published Public Library of Science 26.07.2012
Subjects
Health aspects
Pneumonia
Pseudomonas aeruginosa
RNA
Virulence (Microbiology)
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Summary:ExoU, a Pseudomonas aeruginosa cytotoxin injected into host cytosol by type III secretion system, exhibits a potent proinflammatory activity that leads to a marked recruitment of neutrophils to infected tissues. To evaluate the mechanisms that account for neutrophil infiltration, we investigated the effect of ExoU on IL-8 secretion and NF-[kappa]B activation. We demonstrate that ExoU increases IL-8 mRNA and protein levels in P. aeruginosa-infected epithelial and endothelial cell lines. Also, ExoU induces the nuclear translocation of p65/p50 NF-[kappa]B transactivator heterodimer as well as NF-[kappa]B-dependent transcriptional activity. ChIP assays clearly revealed that ExoU promotes p65 binding to NF-[kappa]B site in IL-8 promoter and the treatment of cultures with the NF-[kappa]B inhibitor Bay 11-7082 led to a significant reduction in IL-8 mRNA levels and protein secretion induced by ExoU. These results were corroborated in a murine model of pneumonia that revealed a significant reduction in KC secretion and neutrophil infiltration in bronchoalveolar lavage when mice were treated with Bay 11-7082 before infection with an ExoU-producing strain. In conclusion, our data demonstrate that ExoU activates NF-[kappa]B, stimulating IL-8 expression and secretion during P. aeruginosa infection, and unveils a new mechanism triggered by this important virulence factor to interfere in host signaling pathways.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0041772