title: Akt-mediated proinflammatory response of mononuclear phagocytes infected with Burkholderia cenocepacia occurs by a novel GSK3β-dependent, IκB kinase-independent mechanism.
abstract: The environmental bacterium Burkholderia cenocepacia causes opportunistic lung infections in immunocompromised individuals, particularly in patients with cystic fibrosis. Infections in these patients are associated with exacerbated inflammation leading to rapid decay of lung function, and in some cases resulting in cepacia syndrome, which is characterized by a fatal acute necrotizing pneumonia and sepsis. B. cenocepacia can survive intracellularly in macrophages by altering the maturation of the phagosome, but very little is known on macrophage responses to the intracellular infection. In this study, we have examined the role of the PI3K/Akt signaling pathway in B. cenocepacia-infected monocytes and macrophages. We show that PI3K/Akt activity was required for NF-κB activity and the secretion of proinflammatory cytokines during infection with B. cenocepacia. In contrast to previous observations in epithelial cells infected with other Gram-negative bacteria, Akt did not enhance IκB kinase or NF-κB p65 phosphorylation, but rather inhibited GSK3β, a negative regulator of NF-κB transcriptional activity. This novel mechanism of modulation of NF-κB activity may provide a unique therapeutic target for controlling excessive inflammation upon B. cenocepacia infection.
authors.affiliation: Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cremer
authors.forename: Prexy
authors.initials: P
authors.lastname: Shah
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valvano
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
mesh_terms: D000818:Animals; D019121:Burkholderia Infections / Q000276:immunology* / Q000473:pathology; D057508:Burkholderia cenocepacia / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors
chemical_list: D018836:Inflammation Mediators; D051996:Transcription Factor RelA; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3