SHIP1 is a repressor of mast cell hyperplasia, cytokine production, and allergic inflammation in vivo.
SHIP1 inhibits immune receptor signaling through hydrolysis of the PI3K product phosphatidylinositol 3,4,5-trisphosphate, forming phosphatidylinositol 3,4-bisphosphate. In mast cells, SHIP1 represses FcepsilonRI- and cytokine-mediated activation in vitro, but little is known regarding the function of SHIP1 in mast cells in vivo or the susceptibility of Ship1(-/-) mice to mast cell-associated diseases. In this study, we found that Ship1(-/-) mice have systemic mast cell hyperplasia, increased serum levels of IL-6, TNF, and IL-5, and heightened anaphylactic response. Further, by reconstituting mast cell-deficient mice with Ship1(+/+) or Ship1(-/-) mast cells, we found that the above defects were due to loss of SHIP1 in mast cells. Additionally, we found that mice reconstituted with Ship1(-/-) mast cells suffered worse allergic asthma pathology than those reconstituted with Ship1(+/+) mast cells. In summary, our data show that SHIP1 represses allergic inflammation and mast cell hyperplasia in vivo and exerts these effects specifically in mast cells.
Haddon
D James
DJ
The Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Antignano
Frann
F
Hughes
Michael R
MR
Blanchet
Marie-Renée
MR
Zbytnuik
Lori
L
Krystal
Gerald
G
McNagny
Kelly M
KM
D000707:Anaphylaxis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000502:physiology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008407:Mast Cells / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D018836:Inflammation Mediators; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases