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Science 287 (5455): 1049-1053

Copyright © 2000 by the American Association for the Advancement of Science

Central Role for G Protein-Coupled Phosphoinositide 3-Kinase gamma  in Inflammation

Emilio Hirsch, 1* Vladimir L. Katanaev, 2 Cecilia Garlanda, 3 Ornella Azzolino, 1 Luciano Pirola, 2 Lorenzo Silengo, 1 Silvano Sozzani, 3 Alberto Mantovani, 34 Fiorella Altruda, 1dagger Matthias P. Wymann 2*dagger

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma -/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma -null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

1 Department of Genetics, Biology and Biochemistry, University of Torino, Turin, Italy.
2 Institute of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland.
3 Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
4 Section of General Pathology, University of Brescia, Brescia, Italy.
*   To whom correspondence should be addressed. E-mail: hirsch{at}molinette.unito.it and matthiaspaul.wymann{at}unifr.ch

dagger    These authors contributed equally to this work.

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Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum.
D. M. Veltman, I. Keizer-Gunnik, and P. J.M. Van Haastert (2008)
J. Cell Biol. 180, 747-753
   Abstract »    Full Text »    PDF »
Critical Roles of the p110{beta} Subtype of Phosphoinositide 3-Kinase in Lipopolysaccharide-Induced Akt Activation and Negative Regulation of Nitrite Production in RAW 264.7 Cells.
K. Tsukamoto, K. Hazeki, M. Hoshi, K. Nigorikawa, N. Inoue, T. Sasaki, and O. Hazeki (2008)
J. Immunol. 180, 2054-2061
   Abstract »    Full Text »    PDF »
Selective Regulation of CD8 Effector T Cell Migration by the p110{gamma} Isoform of Phosphatidylinositol 3-Kinase.
A. L. Martin, M. D. Schwartz, S. C. Jameson, and Y. Shimizu (2008)
J. Immunol. 180, 2081-2088
   Abstract »    Full Text »    PDF »
Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110{delta} but Not p110{gamma} Promotes Optimal Allergic Responses In Vivo.
K. Ali, M. Camps, W. P. Pearce, H. Ji, T. Ruckle, N. Kuehn, C. Pasquali, C. Chabert, C. Rommel, and B. Vanhaesebroeck (2008)
J. Immunol. 180, 2538-2544
   Abstract »    Full Text »    PDF »
The Molecular Basis of VEGFR-1 Signal Transduction Pathways in Primary Human Monocytes.
V. Tchaikovski, G. Fellbrich, and J. Waltenberger (2008)
Arterioscler Thromb Vasc Biol 28, 322-328
   Abstract »    Full Text »    PDF »
Small Molecule Disruption of G Protein {beta}{gamma} Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation.
D. M. Lehmann, A. M. P. B. Seneviratne, and A. V. Smrcka (2008)
Mol. Pharmacol. 73, 410-418
   Abstract »    Full Text »    PDF »
CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer.
F. Garcon, D. T. Patton, J. L. Emery, E. Hirsch, R. Rottapel, T. Sasaki, and K. Okkenhaug (2008)
Blood 111, 1464-1471
   Abstract »    Full Text »    PDF »
PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP.
B. Heit, L. Liu, P. Colarusso, K. D. Puri, and P. Kubes (2008)
J. Cell Sci. 121, 205-214
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase {gamma} Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions.
P. Madeddu, N. Kraenkel, L. S. Barcelos, M. Siragusa, P. Campagnolo, A. Oikawa, A. Caporali, A. Herman, O. Azzolino, L. Barberis, et al. (2008)
Arterioscler Thromb Vasc Biol 28, 68-76
   Abstract »    Full Text »    PDF »
PDZRhoGEF and myosin II localize RhoA activity to the back of polarizing neutrophil-like cells.
K. Wong, A. Van Keymeulen, and H. R. Bourne (2007)
J. Cell Biol. 179, 1141-1148
   Abstract »    Full Text »    PDF »
Formyl Peptide Receptor-1 Activation Enhances Intestinal Epithelial Cell Restitution through Phosphatidylinositol 3-Kinase-Dependent Activation of Rac1 and Cdc42.
B. A. Babbin, A. J. Jesaitis, A. I. Ivanov, D. Kelly, M. Laukoetter, P. Nava, C. A. Parkos, and A. Nusrat (2007)
J. Immunol. 179, 8112-8121
   Abstract »    Full Text »    PDF »
Tissue- and Stimulus-Dependent Role of Phosphatidylinositol 3-Kinase Isoforms for Neutrophil Recruitment Induced by Chemoattractants In Vivo.
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. (2007)
J. Immunol. 179, 7891-7898
   Abstract »    Full Text »    PDF »
The acute-phase protein {alpha}1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (Siglecs).
P. Gunnarsson, L. Levander, P. Pahlsson, and M. Grenegard (2007)
FASEB J 21, 4059-4069
   Abstract »    Full Text »    PDF »
Endothelial PI 3-kinase activity regulates lymphocyte diapedesis.
M. Nakhaei-Nejad, A. M. Hussain, Q.-X. Zhang, and A. G. Murray (2007)
Am J Physiol Heart Circ Physiol 293, H3608-H3616
   Abstract »    Full Text »    PDF »
Phosphoinositide 3 kinase {gamma} participates in T cell receptor induced T cell activation.
I. Alcazar, M. Marques, A. Kumar, E. Hirsch, M. Wymann, A. C. Carrera, and D. F. Barber (2007)
J. Exp. Med. 204, 2977-2987
   Abstract »    Full Text »    PDF »
G{alpha}i2 is required for chemokine-induced neutrophil arrest.
A. Zarbock, T. L. Deem, T. L. Burcin, and K. Ley (2007)
Blood 110, 3773-3779
   Abstract »    Full Text »    PDF »
The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion.
N. Kim, A. Saudemont, L. Webb, M. Camps, T. Ruckle, E. Hirsch, M. Turner, and F. Colucci (2007)
Blood 110, 3202-3208
   Abstract »    Full Text »    PDF »
Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes.
G. Shi, S. Partida-Sanchez, R. S. Misra, M. Tighe, M. T. Borchers, J. J. Lee, M. I. Simon, and F. E. Lund (2007)
J. Exp. Med. 204, 2705-2718
   Abstract »    Full Text »    PDF »

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