SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

• Published in: The Journal of immunology (1950) Vol. 183; no. 1; pp. 228 - 236
• Main Authors: Haddon, D. James, Antignano, Frann, Hughes, Michael R, Blanchet, Marie-Renee, Zbytnuik, Lori, Krystal, Gerald, McNagny, Kelly M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.07.2009
• Subjects: Anaphylaxis - enzymology; Anaphylaxis - genetics; Anaphylaxis - pathology; Animals; Cells, Cultured; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Cytokines - physiology; Female; Hyperplasia - enzymology; Hyperplasia - genetics; Hyperplasia - prevention & control; Hypersensitivity - enzymology; Hypersensitivity - genetics; Hypersensitivity - pathology; Hypersensitivity - prevention & control; Inflammation Mediators - physiology; Inositol Polyphosphate 5-Phosphatases; Mast Cells - enzymology; Mast Cells - pathology; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900427

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.