Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP

PLoS Pathog. 2006 Jul;2(7):e71. doi: 10.1371/journal.ppat.0020071.


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 NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Down-Regulation
  • Francisella*
  • Gram-Negative Bacterial Infections / metabolism*
  • Gram-Negative Bacterial Infections / pathology*
  • Inflammation Mediators / metabolism*
  • Inositol Polyphosphate 5-Phosphatases
  • Interleukin-10 / biosynthesis
  • Macrophages / metabolism*
  • Mice
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoric Monoester Hydrolases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism


  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Interleukin-10
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases