Optimal Chemotactic Responses of Leukemic T Cells to Stromal Cell-Derived Factor-1 Requires the Activation of Both Class IA and IB Phosphoinositide 3-Kinases
| Autor: | Karen L. Wright, Adam P. Curnock, Yannis Sotsios, Stephen G. Ward |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Chemokine
Swine Morpholines Genetic Vectors Immunology Protein Serine-Threonine Kinases P110α Jurkat cells Jurkat Cells Phosphatidylinositol 3-Kinases chemistry.chemical_compound T-Lymphocyte Subsets Proto-Oncogene Proteins Animals Class Ib Phosphatidylinositol 3-Kinase Humans Immunology and Allergy Stromal cell-derived factor 1 LY294002 Enzyme Inhibitors Insulin-Like Growth Factor I Protein kinase A Phosphoinositide-3 Kinase Inhibitors Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 biology Kinase Drug Synergism Chemotaxis Tetracycline Chemokine CXCL12 Clone Cells Cell biology Enzyme Activation Isoenzymes Chemotaxis Leukocyte Gene Expression Regulation chemistry Chromones Cell Migration Inhibition biology.protein Cattle Mitogen-Activated Protein Kinases Chemokines CXC Proto-Oncogene Proteins c-akt |
| Zdroj: | Lancaster University-Pure |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.170.8.4021 |
| Popis: | Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are a multifunctional chemokine/receptor system with essential roles in the development of the immune system and other aspects of embryogenesis, including vascularization and organ development. SDF-1 is also a potent chemoattractant for T cells and has roles in both inflammation and immune homeostasis. Our group has previously demonstrated that phosphoinositide 3-kinase (PI 3-kinase) is activated in SDF-1-stimulated T cells and is indeed required for SDF-1-mediated chemotaxis. In this study Jurkat clones were established, stably expressing dominant negative constructs of class IA and class IB PI 3-kinases under the control of the tetracycline off inducible gene system, to determine the relative roles of these PI 3-kinases in SDF-1 signaling. Our results show that expression of either kinase-dead PI3Kγ (KD-PI3Kγ) or Δp85 (a construct unable to bind class IA p110α, -β, or -δ) leads to a partial inhibition of SDF-1-stimulated protein kinase B phosphorylation, but had no effect on SDF-1-induced phosphorylation of the mitogen-activated protein kinase ERK1/2. Functional studies demonstrated that expression of KD-PI3Kγ markedly inhibited SDF-1-mediated chemotaxis, typically eliciting 40–60% inhibition. Interestingly, the expression of Δp85 also leads to inhibition of the SDF-1-mediated chemotactic response, albeit to a much lesser extent than achieved with the KD-PI3Kγ mutant, typically in the range of 20–40% inhibition. Furthermore, the inhibition of chemotaxis by the expression of dominant negative class IA or class IB PI 3-kinases could be enhanced by the presence of the PI 3-kinase inhibitor LY294002. Together, these results demonstrate that optimal chemotactic response of leukemic T cells to SDF-1 requires the activation of both class IA and class IB PI 3-kinases. |
| Databáze: | OpenAIRE |
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