Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.
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.
Parsa
Kishore V L
KV
The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio, USA.
Ganesan
Latha P
LP
Rajaram
Murugesan V S
MV
Gavrilin
Mikhail A
MA
Balagopal
Ashwin
A
Mohapatra
Nrusingh P
NP
Wewers
Mark D
MD
Schlesinger
Larry S
LS
Gunn
John S
JS
Tridandapani
Susheela
S
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005603:Francisella; D016905:Gram-Negative Bacterial Infections / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D016753:Interleukin-10 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases