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