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Blood, 15 July 2006, Vol. 108, No. 2, pp. 718-725. Prepublished online as a Blood First Edition Paper on March 16, 2006; DOI 10.1182/blood-2005-09-3889. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-09-3889v1 108/2/718    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ganesan, L. P. Articles by Tridandapani, S. Search for Related Content PubMed PubMed Citation Articles by Ganesan, L. P. Articles by Tridandapani, S. Related Collections Phagocytes Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES FcR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways Latha P. Ganesan, Trupti Joshi, Huiqing Fang, Vijay Kumar Kutala, Julie Roda, Rossana Trotta, Amy Lehman, Periannan Kuppusamy, John C. Byrd, William E. Carson, Michael A. Caligiuri, and Susheela Tridandapani From the Department of Internal Medicine and Comprehensive Cancer Center; The Ohio State University Biochemistry Program; Department of Molecular Virology, Immunology, and Medical Genetics; and Biostatistics Program, The Ohio State University, Columbus. Phagocytosis of IgG-coated particles via FcR is accompanied by the generation of superoxide and inflammatory cytokines, which can cause collateral tissue damage in the absence of regulation. Molecular mechanisms regulating these phagocytosis-associated events are not known. SHIP is an inositol phosphatase that downregulates PI3K-mediated activation events. Here, we have examined the role of SHIP in FcR-induced production of superoxide and inflammatory cytokines. We report that primary SHIP-deficient bone marrow macrophages produce elevated levels of superoxide upon FcR clustering. Analysis of the molecular mechanism revealed that SHIP regulates upstream Rac-GTP binding, an obligatory event for superoxide production. Likewise, SHIP-deficient macrophages displayed enhanced IL-1 and IL-6 production in response to FcR clustering. Interestingly, whereas IL-6 production required activation of both PI3K and Ras/Erk pathways, IL-1 production was dependent only on Ras/Erk activation, suggesting that SHIP may also regulate the Ras/Erk pathway in macrophages. Consistently, SHIP-deficient macrophages displayed enhanced activation of Erk upon FcR clustering. Inhibition of Ras/Erk or PI3K suppressed the enhanced production of IL-6 in SHIP-deficient macrophages. In contrast, inhibition of Ras/Erk, but not PI3K, suppressed IL-1 production in these cells. Together, these data demonstrate that SHIP regulates phagocytosis-associated events through the inhibition of PI3K and Ras/Erk pathways. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Mehta, M. Glogauer, S. Becart, A. Altman, and K. M. Coggeshall Adaptor Protein SLAT Modulates Fc{gamma} Receptor-mediated Phagocytosis in Murine Macrophages J. Biol. Chem., May 1, 2009; 284(18): 11882 - 11891. [Abstract] [Full Text] [PDF] L. A. Kamen, J. Levinsohn, A. Cadwallader, S. Tridandapani, and J. A. Swanson SHIP-1 Increases Early Oxidative Burst and Regulates Phagosome Maturation in Macrophages J. Immunol., June 1, 2008; 180(11): 7497 - 7505. [Abstract] [Full Text] [PDF]

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