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SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo¹

D. James Haddon^*, Frann Antignano^2,, Michael R. Hughes^2,*, Marie-Renée Blanchet^*, Lori Zbytnuik^*, Gerald Krystal and Kelly M. McNagny^3,*

^* The Biomedical Research Centre and Terry Fox Laboratory, University of British Columbia, Vancouver, British Columbia, Canada

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 FcRI- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by operating grants from the Canadian Institutes for Health Research (CIHR) and AllerGen Network Centre of Excellence. D.J.H. was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the University of British Columbia (UBC) Faculty of Medicine. F.A. was supported by NSERC, the UBC Faculty of Medicine, and the Michael Smith Foundation for Health Research (MSFHR). M.R.H. was supported by the UBC Centre for Blood Research CIHR/Heart and Stroke Foundation of Canada Strategic Training Program in Transfusion Science. M.-R.B. was supported through the CIHR/Canadian Asthma, Allergy and Immunology Foundation Training Program. K.M.M. is a MSFHR Senior Scholar.

D.J.H. designed and performed research, analyzed and interpreted data, and wrote the manuscript. F.A. and M.R.H. designed and performed research, analyzed and interpreted data, and edited the manuscript. M.-R.B. and L.Z. performed research. G.K. and K.M.M. analyzed and interpreted data and edited the manuscript.

² F.A. and M.R.H. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Kelly M. McNagny, The Biomedical Research Centre, 2222 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3 Canada. E-mail address: kelly{at}brc.ubc.ca

⁴ Abbreviations used in this paper: SCF, stem cell factor; BAL, bronchoalveolar lavage; BMMC, bone marrow cultured mast cells; HSA, human serum albumin; PSA, passive systemic anaphylaxis.

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The JI 2009 183: 1-2. [Full Text]