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Blood, 26 March 2009, Vol. 113, No. 13, pp. 2945-2954. Prepublished online as a Blood First Edition Paper on January 12, 2009; DOI 10.1182/blood-2008-06-166082. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-06-166082v1 113/13/2945    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sly, L. M. Articles by Krystal, G. Search for Related Content PubMed PubMed Citation Articles by Sly, L. M. Articles by Krystal, G. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY SHIP prevents lipopolysaccharide from triggering an antiviral response in mice Laura M. Sly1, Melisa J. Hamilton1, Etsushi Kuroda1, Victor W. Ho1, Frann L. Antignano1, Stephanie L. Omeis1, Christina J. van Netten-Thomas1, Dana Wong1, Hayley K. Brugger1, Olusegun Williams2, Morris E. Feldman2, Benjamin T. Houseman2, Dorothea Fiedler2, Kevan M. Shokat2, and Gerald Krystal1 1 Terry Fox Laboratory, British Columbia Cancer Research Centre, British Columbia Cancer Agency, Vancouver, BC; and 2 Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain–containing adaptor-inducing interferon β (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5'-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-β (TGFβ). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)– and LPS-induced tolerance and cross-tolerance and restrains IFN-β production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPS- or cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110, -, and - but negatively regulated by p110β. This may explain some of the controversy concerning the role of PI3K in Toll-like receptor–induced cytokine production. Consistent with our in vitro findings, SHIP–/– mice overproduce IFN-β in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. P. Herbert, J. Huisken, T. N. Kim, M. E. Feldman, B. T. Houseman, R. A. Wang, K. M. Shokat, and D. Y. R. Stainier Arterial-Venous Segregation by Selective Cell Sprouting: An Alternative Mode of Blood Vessel Formation Science, October 9, 2009; 326(5950): 294 - 298. [Abstract] [Full Text] [PDF]

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