HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print September 22, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0306227v1 80/6/1491    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, D. F. Articles by Ley, K. Search for Related Content PubMed PubMed Citation Articles by Smith, D. F. Articles by Ley, K.

(Journal of Leukocyte Biology. 2006;80:1491-1499.)
© 2006 by Society for Leukocyte Biology

Leukocyte phosphoinositide-3 kinase is required for chemokine-induced, sustained adhesion under flow in vivo

David F. Smith^*,1, Tracy L. Deem^,1, Anthony C. Bruce, Jörg Reutershan, Daniel Wu and Klaus Ley^,,2

Departments of
^* Molecular Physiology and Biophysics and
Biomedical Engineering, and
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA; and
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, USA

² Correspondence: University of Virginia, Robert M. Berne Cardiovascular Research Center, MR5 Bldg., Room 1013, P.O. Box 801394, Charlottesville, VA 22908-1394, USA. E-mail: klausley{at}virginia.edu

During inflammation, leukocytes roll along the wall of postcapillary venules scanning the surface for immobilized CXCL1, a chemokine that triggers firm adhesion by activating CXCR2 on the neutrophil. PI-3K are signaling molecules important in cellular processes, ranging from cellular differentiation to leukocyte migration. PI-3K can be activated directly by the β dimer of heterotrimeric G proteins coupled to CXCR2. Here, we used in vivo and ex vivo intravital microscopy models to test the role of PI-3K in leukocyte arrest. PI-3K null mice showed an 80% decrease in CXCL1-induced leukocyte adhesion in venules of the exteriorized mouse cremaster muscle. In wild-type mice, rolling leukocytes showed rapid and sustained adhesion, but in PI-3K^–/– mice, adhesion was not triggered at all or was transient, suggesting that absence of PI-3K interferes with integrin bond strengthening. Wild-type mice reconstituted with PI-3K null bone marrow showed a 50% decrease in CXCL1-induced leukocyte adhesion. In a blood-perfused micro-flow chamber, leukocytes from PI-3K^–/– mice showed a defect in adhesion on a P-selectin/ICAM-1/CXCL1 substrate, indicating that leukocyte PI-3K was required for adhesion. The adhesion defect in PI-3K^–/– mice was as severe as that in mice lacking LFA-1, the major integrin responsible for neutrophil adhesion. We conclude that the isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation.

Key Words: signal transduction • cell trafficking • inflammation

This article has been cited by other articles:

				A. Zarbock, C. L. Abram, M. Hundt, A. Altman, C. A. Lowell, and K. Ley PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR{gamma} to induce slow leukocyte rolling J. Exp. Med., September 29, 2008; 205(10): 2339 - 2347. [Abstract] [Full Text] [PDF]

				M. S. Thomas, J. S. Mitchell, C. C. DeNucci, A. L. Martin, and Y. Shimizu The p110{gamma} isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites J. Leukoc. Biol., September 1, 2008; 84(3): 814 - 823. [Abstract] [Full Text] [PDF]

				D. Frommhold, A. Ludwig, M. G. Bixel, A. Zarbock, I. Babushkina, M. Weissinger, S. Cauwenberghs, L. G. Ellies, J. D. Marth, A. G. Beck-Sickinger, et al. Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation J. Exp. Med., June 9, 2008; 205(6): 1435 - 1446. [Abstract] [Full Text] [PDF]

				S. M. Kerfoot, G. Andonegui, C. S. Bonder, and L. Liu Exogenous stromal cell-derived factor-1 induces modest leukocyte recruitment in vivo Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2524 - H2534. [Abstract] [Full Text] [PDF]

				E. Chavakis, G. Carmona, C. Urbich, S. Gottig, R. Henschler, J. M. Penninger, A. M. Zeiher, T. Chavakis, and S. Dimmeler Phosphatidylinositol-3-Kinase-{gamma} Is Integral to Homing Functions of Progenitor Cells Circ. Res., April 25, 2008; 102(8): 942 - 949. [Abstract] [Full Text] [PDF]

				B. Heit, L. Liu, P. Colarusso, K. D. Puri, and P. Kubes PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP J. Cell Sci., January 15, 2008; 121(2): 205 - 214. [Abstract] [Full Text] [PDF]

				A. Zarbock and K. Ley Mechanisms and Consequences of Neutrophil Interaction with the Endothelium Am. J. Pathol., January 1, 2008; 172(1): 1 - 7. [Abstract] [Full Text] [PDF]

				V. Pinho, R. de Castro Russo, F. A. Amaral, L. P. de Sousa, M. M. Barsante, D. G. de Souza, J. C. Alves-Filho, D. C. Cara, J. S. Hayflick, C. Rommel, et al. Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3-Kinase Isoforms for Neutrophil Recruitment Induced by Chemoattractants In Vivo J. Immunol., December 1, 2007; 179(11): 7891 - 7898. [Abstract] [Full Text] [PDF]

				A. Zarbock, T. L. Deem, T. L. Burcin, and K. Ley G{alpha}i2 is required for chemokine-induced neutrophil arrest Blood, November 15, 2007; 110(10): 3773 - 3779. [Abstract] [Full Text] [PDF]

				L. Liu, K. D. Puri, J. M. Penninger, and P. Kubes Leukocyte PI3K{gamma} and PI3K{delta} have temporally distinct roles for leukocyte recruitment in vivo Blood, August 15, 2007; 110(4): 1191 - 1198. [Abstract] [Full Text] [PDF]