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Akt-mediated proinflammatory response of mononuclear phagocytes infected with Burkholderia cenocepacia occurs by a novel GSK3β-dependent, IκB kinase-independent mechanism.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2011 Jul 15; Vol. 187 (2), pp. 635-43. Date of Electronic Publication: 2011 Jun 22. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Burkholderia Infections pathology
Down-Regulation immunology
Glycogen Synthase Kinase 3 antagonists & inhibitors
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
Humans
Macrophages microbiology
Macrophages pathology
Mice
Monocytes microbiology
Monocytes pathology
Phosphatidylinositol 3-Kinases physiology
Phosphorylation immunology
Signal Transduction immunology
Transcription Factor RelA antagonists & inhibitors
Burkholderia Infections immunology
Burkholderia cenocepacia immunology
Glycogen Synthase Kinase 3 physiology
I-kappa B Kinase physiology
Inflammation Mediators physiology
Macrophages immunology
Monocytes immunology
Proto-Oncogene Proteins c-akt physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 187
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 21697459
- Full Text :
- https://doi.org/10.4049/jimmunol.1003034