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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3448-3456. Prepublished online as a Blood First Edition Paper on January 29, 2004; DOI 10.1182/blood-2003-05-1667. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1667v1 103/9/3448    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 Puri, K. D. Articles by Diacovo, T. G. Search for Related Content PubMed PubMed Citation Articles by Puri, K. D. Articles by Diacovo, T. G. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Phagocytes Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Mechanisms and implications of phosphoinositide 3-kinase in promoting neutrophil trafficking into inflamed tissue Kamal D. Puri, Teresa A. Doggett, Jason Douangpanya, Yonghao Hou, William T. Tino, Tim Wilson, Thomas Graf, Elizabeth Clayton, Martin Turner, Joel S. Hayflick, and Thomas G. Diacovo From ICOS, Bothell, WA; the Division of Newborn Medicine, Department of Pediatrics and the Department of Pathology, Washington University and St Louis Children's Hospital, St Louis, MO; the Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; and the Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge, United Kingdom. The phosphoinositide 3-kinase (PI3K) catalytic subunit p110 is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110 is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor (TNF). Specifically, administration of the selective inhibitor of PI3K, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K in TNF-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110 expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium. (Blood. 2004;103:3448-3456) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. M. Randis, N. Diacovo, J. Calafat, and T. G. 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