{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:55:46Z","timestamp":1792133746425,"version":"4.4.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We report that SHIP\u2212\/\u2212 mice, compared to SHIP+\/+ mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4+ Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-\u03b3. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP\u2212\/\u2212 splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to Fc\u03b5RI stimulation than do WT basophils. These SHIP\u2212\/\u2212 basophils markedly skew wild-type macrophage colony stimulating factor\u2013derived macrophages toward an M2 phenotype, stimulate OT-II CD4+ Th cells to differentiate into Th2 cells, and trigger SHIP+\/+ B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti\u2013IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP\u2212\/\u2212 basophils, we found that IL-3\u2013induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110\u03b1 inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP+\/+ and SHIP\u2212\/\u2212 mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.1002778","type":"journal-article","created":{"date-parts":[[2010,12,4]],"date-time":"2010-12-04T05:24:20Z","timestamp":1291440260000},"page":"323-332","source":"Crossref","is-referenced-by-count":25,"title":["SHIP Represses Th2 Skewing by Inhibiting IL-4 Production from Basophils"],"prefix":"10.1093","volume":"186","author":[{"given":"Etsushi","family":"Kuroda","sequence":"first","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]},{"name":"Department of Immunology and Parasitology, University of Occupational and Environmental Health, School of Medicine , Kitakyushu ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frann","family":"Antignano","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]},{"name":"Biomedical Research Centre, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor W","family":"Ho","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"Hughes","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Ruschmann","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]},{"name":"Fachbereich Biologie, Chemie, Pharmazie, Freie Universit\u00e4t-Berlin , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Lam","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G","family":"Kerr","sequence":"additional","affiliation":[{"name":"State University of New York Upstate Medical University , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly M","family":"McNagny","sequence":"additional","affiliation":[{"name":"Biomedical Research Centre, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M","family":"Sly","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]},{"name":"Division of Gastroenterology, Department of Pediatrics, BC Children\u2019s Hospital, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Krystal","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,1,1]]},"reference":[{"key":"2025032410573650800_r1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/00062752-200101000-00009","article-title":"Th1 and Th2 cells","volume":"8","author":"Dong","year":"2001","journal-title":"Curr. 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