Journal
PLOS PATHOGENS
Volume 2, Issue 7, Pages 681-690Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.0020071
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Funding
- NCI NIH HHS [P01 CA095426] Funding Source: Medline
- NIAID NIH HHS [U54-AI-057153, U54 AI057153, R01 AI059406] Funding Source: Medline
- PHS HHS [T32 0155411] Funding Source: Medline
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Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase ( SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/ Akt resulted in suppression of F. novicida induced cytokine production through the inhibition of NF kappa B. Consistently, macrophages lacking SHIP displayed enhanced NF kappa B-driven gene transcription, whereas overexpression of SHIP led to decreased NF kappa B activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NF kappa B-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.
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