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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5202-5211. Prepublished online as a Blood First Edition Paper on August 28, 2008; DOI 10.1182/blood-2008-04-149450. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-04-149450v1 112/13/5202    most recent Alert me when this article is cited Alert me if a correction is posted 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 Anderson, K. E. Articles by Hawkins, P. T. Search for Related Content PubMed PubMed Citation Articles by Anderson, K. E. Articles by Hawkins, P. T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 4, 2008 Accepted August 22, 2008 CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of E.coli or S.aureus is regulated by Class III but not Class I or II PI3Ks Karen E. Anderson, Keith Boyle, Keith Davidson, Tamara A.-M. Chessa, Suhasini Kulkarni, Gavin E. Jarvis, Anca Sindrilaru, Karin Scharffetter-Kochanek, Oliver Rausch, Len R. Stephens, and Phillip T. Hawkins* Inositide Laboratory, Babraham Institute, Cambridge, United Kingdom Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom Klinik fur Dermatologie und Allergologie, Universitatsklinikum Ulm Maienweg, Ulm, Germany UCB Celltech, Great Abington, Cambridge, United Kingdom * Corresponding author; email: phillip.hawkins{at}bbsrc.ac.uk. Phagocytosis and activation of the NADPH oxidase are important mechanisms by which neutrophils and macrophages engulf and kill microbial pathogens. We investigated the role of PI3K signalling pathways in the regulation of the oxidase during phagocytosis of S.aureus and E.coli by mouse and human neutrophils, a mouse macrophage-like cell line and a human myeloid-like cell line. Phagocytosis of these bacteria was promoted by serum, independent of serum-derived antibodies, and almost totally abolished in mouse neutrophils lacking the 2-integrin common chain, CD18. A combination of PI3K isoform-selective inhibitors, mouse knock-outs and RNA-interference indicated CD18-dependent activation of the oxidase was independent of Class I and II PI3Ks, but substantially dependent on the single Class III isoform (Vps34). Class III PI3K was responsible for the synthesis of PtdIns(3)P on both S.aureus- and E.coli-containing phagosomes. The use of mouse neutrophils carrying a knock-in mutation in the PX domain of their p40phox oxidase subunit indicated that PtdIns(3)P binding to the p40phox-PX domain is important for oxidase activation in response to both S.aureus and E.coli. This interaction does not however, account for all the PI3K sensitivity of these responses, particularly the oxidase response to E.coli, suggesting that additional mechanisms for PtdIns(3)P-regulation of the oxidase must exist. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: PI3K and NADPH oxidase: a class act Adam D. Kennedy and Frank R. DeLeo Blood 2008 112: 4788-4789. [Full Text] [PDF] This article has been cited by other articles: J. D. Matute, A. A. Arias, N. A. M. Wright, I. Wrobel, C. C. M. Waterhouse, X. J. Li, C. C. Marchal, N. D. Stull, D. B. Lewis, M. Steele, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity Blood, October 8, 2009; 114(15): 3309 - 3315. [Abstract] [Full Text] [PDF] Y. Li, Y. Jia, M. Pichavant, F. Loison, B. Sarraj, A. Kasorn, J. You, B. E. Robson, D. T. Umetsu, J. P. Mizgerd, et al. Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia Blood, May 14, 2009; 113(20): 4930 - 4941. [Abstract] [Full Text] [PDF]

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