SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.
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.
Sly
Laura M
LM
Terry Fox Laboratory, British Columbia Cancer Research Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
Hamilton
Melisa J
MJ
Kuroda
Etsushi
E
Ho
Victor W
VW
Antignano
Frann L
FL
Omeis
Stephanie L
SL
van Netten-Thomas
Christina J
CJ
Wong
Dana
D
Brugger
Hayley K
HK
Williams
Olusegun
O
Feldman
Morris E
ME
Houseman
Benjamin T
BT
Fiedler
Dorothea
D
Shokat
Kevan M
KM
Krystal
Gerald
G
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*
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