title: ExoU activates NF-κB and increases IL-8/KC secretion during Pseudomonas aeruginosa infection.
abstract: 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-κB 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-κB transactivator heterodimer as well as NF-κB-dependent transcriptional activity. ChIP assays clearly revealed that ExoU promotes p65 binding to NF-κB site in IL-8 promoter and the treatment of cultures with the NF-κB 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-κB, 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.
authors: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Carolina Diettrich Mallet
authors: CD
authors: de Lima
authors: Teresa Cristina
authors: TC
authors: Calegari-Silva
authors: Renata Meirelles Santos
authors: RM
authors: Pereira
authors: Sabrina Alves de Oliveira Lima
authors: SA
authors: Santos
authors: Ulisses Gazos
authors: UG
authors: Lopes
authors: Maria-Cristina Maciel
authors: MC
authors: Plotkowski
authors: Alessandra Mattos
authors: AM
authors: Saliba
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology; D002196:Capillaries / Q000166:cytology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000276:immunology / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa