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...

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Main 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
Format:	Online
Language:	English
Published:	Public Library of Science 2006
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513262/

id	pubmed-1513262
recordtype	oai_dc
spelling	pubmed-15132622006-07-20 Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP 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 Research Article 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. Public Library of Science 2006-07 2006-07-21 /pmc/articles/PMC1513262/ /pubmed/16848641 http://dx.doi.org/10.1371/journal.ppat.0020071 Text en © 2006 Parsa et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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 Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
author_facet	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
author_sort	Parsa, Kishore V. L
title	Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
title_short	Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
title_full	Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
title_fullStr	Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
title_full_unstemmed	Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP
title_sort	macrophage pro-inflammatory response to francisella novicida infection is regulated by ship
description	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.
publisher	Public Library of Science
publishDate	2006
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513262/
_version_	1611384732604432384

Macrophage Pro-Inflammatory Response to Francisella novicida Infection Is Regulated by SHIP

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