title: SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.
abstract: 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 beta (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-beta (TGFbeta). 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-beta 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 p110alpha, -gamma, and -delta but negatively regulated by p110beta. 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-beta 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.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Hamilton
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.forename: Victor W
authors.initials: VW
authors.lastname: Ho
authors.forename: Frann L
authors.initials: FL
authors.lastname: Antignano
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Omeis
authors.forename: Christina J
authors.initials: CJ
authors.lastname: van Netten-Thomas
authors.forename: Dana
authors.initials: D
authors.lastname: Wong
authors.forename: Hayley K
authors.initials: HK
authors.lastname: Brugger
authors.forename: Olusegun
authors.initials: O
authors.lastname: Williams
authors.forename: Morris E
authors.initials: ME
authors.lastname: Feldman
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Houseman
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007035:Hypothermia / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics*; D000072181:Inositol Polyphosphate 5-Phosphatases; D016899:Interferon-beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014780:Viruses / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012330:RNA, Double-Stranded; D016212:Transforming Growth Factor beta; D016899:Interferon-beta; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases