title: Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.
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 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.
authors.affiliation: The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kishore V L
authors.initials: KV
authors.lastname: Parsa
authors.forename: Latha P
authors.initials: LP
authors.lastname: Ganesan
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Gavrilin
authors.forename: Ashwin
authors.initials: A
authors.lastname: Balagopal
authors.forename: Nrusingh P
authors.initials: NP
authors.lastname: Mohapatra
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
mesh_terms: 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
chemical_list: 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