title: Regulation of pulmonary Pseudomonas aeruginosa infection by the transcriptional repressor Gfi1.
abstract: Pulmonary Pseudomonas aeruginosa infections are characterized by the release of proinflammatory mediators, focal induction of apoptosis in respiratory epithelial cells and internalization of the bacteria. Here, we demonstrate that the transcriptional regulator Gfi1 is critically involved in the regulation of proinflammatory cytokine release and the induction of apoptosis in respiratory epithelial cells and macrophages upon P. aeruginosa infection. Gfi1-deficient mice responded to a pulmonary P. aeruginosa infection with uncontrolled pulmonary release of interleukin (IL)-1 and tumour necrosis factor (TNF)-alpha, sepsis and death, which were delayed by injection of IL-1- and TNF-alpha-neutralizing antibodies. The uncontrolled release of cytokines seems to be caused by a failure of Gfi1-deficient respiratory epithelial cells in large to small bronchi and macrophages to respond to P. aeruginosa infection with an induction of apoptosis. Pharmacological inhibition of apoptosis in wild-type mice by intravenous injection of the broad-spectrum caspase inhibitor zVAD-cmk mimicked the phenotype of Gfi1-deficient mice and resulted in a profound sensitization of mice to P. aeruginosa, an increased release of cytokines, sepsis and death of the animals. Thus, Gfi1 controls apoptosis of respiratory epithelial cells and macrophages upon infection with P. aeruginosa. Inhibition of apoptosis by Gfi1 deficiency or caspase blockers sensitizes mice to P. aeruginosa infections, suggesting that apoptosis functions as a novel defence mechanisms in the regulation of the local innate immune response.
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Grassmé
authors.forename: Jianmin
authors.initials: J
authors.lastname: Jin
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilker
authors.forename: Gabriele
authors.initials: G
authors.lastname: von Kürthy
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D007375:Interleukin-1; D012097:Repressor Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha