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Department of Pharmacy and Pharmacology, Bath University, Claverton Down, Bath, Avon, United Kingdom
The cellular effects of stromal cell-derived factor-1 (SDF-1) are mediated primarily by binding to the CXC chemokine receptor-4. We report in this study that SDF-1 and its peptide analogues induce a concentration- and time-dependent accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P3) in Jurkat cells. This SDF-1-stimulated generation of D-3 phosphoinositide lipids was inhibited by pretreatment of the cells with an SDF-1 peptide antagonist or an anti-CXCR4 Ab. In addition, the phosphoinositide 3 (PI 3)-kinase inhibitors wortmannin and LY294002, as well as the Gi protein inhibitor pertussis toxin, also inhibited the SDF-1-stimulated accumulation of PtdIns(3,4,5)P3. The effects of SDF-1 on D-3 phosphoinositide lipid accumulation correlated well with activation of the known PI 3-kinase effector protein kinase B, which was also inhibited by wortmannin and pertussis toxin. Concentrations of PI 3-kinase inhibitors, sufficient to inhibit PtdIns(3,4,5)P3 accumulation, also inhibited chemotaxis of Jurkat and peripheral blood-derived T lymphocytes in response to SDF-1. In contrast, SDF-1-stimulated actin polymerization was only partially inhibited by PI 3-kinase inhibitors, suggesting that while chemotaxis is fully dependent on PI 3-kinase activation, actin polymerization requires additional biochemical inputs. Finally, SDF-1-stimulated extracellular signal-related kinase (ERK)-1/2 mitogen-activated protein kinase activation was inhibited by PI 3-kinase inhibitors. In addition, the mitogen-activated protein/ERK kinase inhibitor PD098059 partially attenuated chemotaxis in response to SDF-1. Hence, it appears that ERK1/2 activation is dependent on PI 3-kinase activation, and both biochemical events are involved in the regulation of SDF-1-stimulated chemotaxis.
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 V. Grabovsky, S. Feigelson, C. Chen, D. A. Bleijs, A. Peled, G. Cinamon, F. Baleux, F. Arenzana-Seisdedos, T. Lapidot, Y. van Kooyk, et al. Subsecond Induction of {alpha}4 Integrin Clustering by Immobilized Chemokines Stimulates Leukocyte Tethering and Rolling on Endothelial Vascular Cell Adhesion Molecule 1 under Flow Conditions J. Exp. Med., August 21, 2000; 192(4): 495 - 506. [Abstract] [Full Text] [PDF]
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T. Nanki and P. E. Lipsky Cutting Edge: Stromal Cell-Derived Factor-1 Is a Costimulator for CD4+ T Cell Activation J. Immunol., May 15, 2000; 164(10): 5010 - 5014. [Abstract] [Full Text] [PDF]
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P. H. Naccache, S. Levasseur, G. Lachance, S. Chakravarti, S. G. Bourgoin, and S. R. McColl Stimulation of Human Neutrophils by Chemotactic Factors Is Associated with the Activation of Phosphatidylinositol 3-Kinase gamma J. Biol. Chem., July 28, 2000; 275(31): 23636 - 23641. [Abstract] [Full Text] [PDF]
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V. Kansra, C. Groves, J. C. Gutierrez-Ramos, and R. D. Polakiewicz Phosphatidylinositol 3-Kinase-dependent Extracellular Calcium Influx Is Essential for CX3CR1-mediated Activation of the Mitogen-activated Protein Kinase Cascade J. Biol. Chem., August 17, 2001; 276(34): 31831 - 31838. [Abstract] [Full Text] [PDF]
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R. E. Gerszten, E. B. Friedrich, T. Matsui, R. R. Hung, L. Li, T. Force, and A. Rosenzweig Role of Phosphoinositide 3-Kinase in Monocyte Recruitment under Flow Conditions J. Biol. Chem., July 13, 2001; 276(29): 26846 - 26851. [Abstract] [Full Text] [PDF]
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