LPS-induced upregulation of SHIP is essential for endotoxin tolerance.
An initial exposure to lipopolysaccharide (LPS) induces a transient state of hyporesponsiveness to a subsequent challenge with LPS. The mechanism underlying this phenomenon, termed endotoxin tolerance, remains poorly understood despite a recent resurgence of interest in this area. We demonstrate herein that SHIP(-/-) bone marrow-derived macrophages (BMmphis) and mast cells (BMMCs) do not display endotoxin tolerance. Moreover, an initial LPS treatment of wild-type BMmphis or BMMCs increases the level of SHIP, but not SHIP2 or PTEN, and this increase is critical for the hyporesponsiveness to subsequent LPS stimulation. Interestingly, this increase in SHIP protein is mediated by the LPS-induced production of autocrine-acting TGFbeta and neutralizing antibodies to TGFbeta block LPS-induced endotoxin tolerance. In vivo studies with SHIP(+/+) and SHIP(-/-) mice confirm these in vitro findings and show a correlation between the duration of endotoxin tolerance and elevated SHIP levels.
Sly
Laura M
LM
The Terry Fox Laboratory, BC Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.
Rauh
Michael J
MJ
Kalesnikoff
Janet
J
Song
Christine H
CH
Krystal
Gerald
G
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases