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- Title
Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP.
- Authors
Parsa, Kishore V. L.; Ganesan, Latha P.; Rajaram, Murugesan V. S.; Gavrilin, Mikhail A.; Balagopal, Ashwin; Mohapatra, Nrusingh P.; Wewers, Mark D.; Schlesinger, Larry S.; Gunn, John S.; Tridandapani, Susheela
- Abstract
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 NFκB. Consistently, macrophages lacking SHIP displayed enhanced NFκB-driven gene transcription, whereas overexpression of SHIP led to decreased NFκB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFκB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.
- Subjects
FRANCISELLA tularensis; INTRACELLULAR pathogens; TULAREMIA; MACROPHAGES; INTERLEUKIN-12; INOSITOL phosphates
- Publication
PLoS Pathogens, 2006, Vol 2, Issue 7, pe71
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.0020071