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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.
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Submitted June 30, 2008
Accepted December 19, 2008
SHIP prevents lipopolysaccharide from triggering an anti-viral response in mice
Laura M. Sly, Melisa J. Hamilton, Etsushi Kuroda, Victor W. Ho, Frann L. Antignano, Stephanie L. Omeis, Christina J. van Netten-Thomas, Dana Wong, Hayley K. Brugger, Olusegun Williams, Morris E. Feldman, Benjamin T. Houseman, Dorothea Fiedler, Kevan M. Shokat, and Gerald Krystal*
The Terry Fox Laboratory, BC Cancer Research Centre, BC Cancer Agency, Vancouver, BC, Canada
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, United States
* Corresponding author; email: gkrystal{at}bccrc.ca.
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 TRIF pathway and thus are both capable of eliciting an anti-viral response by stimulating type I interferon (IFN) production. We demonstrate herein that SHIP protein levels are dramatically increased in murine macrophages only via the MyD88-dependent pathway, by upregulating autocrine-acting TGF . The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, CpG- and LPS-induced tolerance and cross-tolerance and restrains IFN production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform specific PI3K inhibitors, that LPS- or CpG-induced IL-6 is positively regulated by p110 ,  , and  but negatively regulated by . This may explain some of the controversy concerning the role of PI3K in TLR-induced cytokine production. Consistent with our in vitro findings, SHIP-/- mice overproduce IFN in response to LPS and this leads to anti-viral hypothermia. Thus, upregulation of SHIP in response to Gram-negative bacterial infections likely explains the inability of such infections to protect against subsequent viral infections.
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[Abstract]
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