The CysLT1 Ligand Leukotriene D4 Supports α4β1- and α5β1-Mediated Adhesion and Proliferation of CD34+ Hematopoietic Progenitor Cells
| Autor: | Robert Möhle, Tina Wiesner, Gabriele Seitz, Adriana Drost, Lothar Kanz, Andreas M. Boehmler, Lena Jaggy, Claudio Denzlinger |
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| Rok vydání: | 2009 |
| Předmět: |
Chemokine
Stromal cell Leukotriene D4 Immunology CD34 Antigens CD34 Bone Marrow Cells Cell Communication Integrin alpha4beta1 CXCR4 chemistry.chemical_compound Cell Adhesion medicine Humans Immunology and Allergy Phosphorylation Progenitor cell Cell adhesion Cells Cultured Cell Proliferation Receptors Leukotriene biology Hematopoietic Stem Cells Up-Regulation medicine.anatomical_structure chemistry biology.protein Cancer research Bone marrow Stromal Cells Integrin alpha5beta1 |
| Zdroj: | The Journal of Immunology. 182:6789-6798 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Cytokines and chemokines control hematopoietic stem and progenitor cell (HPC) proliferation and trafficking. However, the role of nonpeptide mediators in the bone marrow microenvironment has remained elusive. Particularly CysLT1, a G protein-coupled receptor recognizing inflammatory mediators of the cysteinyl leukotriene family, is highly expressed in HPCs. We therefore analyzed the effects of its ligands on human CD34+ HPCs. The most potent CysLT1 ligand, LTD4, rapidly and significantly up-regulated α4β1 and α5β1 integrin-dependent adhesion of both primitive and committed HPC. LTD4-triggered adhesion was inhibited by specific CysLT1 antagonists. The effects of other CysLT1 ligands were weak (LTC4) or absent (LTE4). In serum-free liquid cultures supplemented with various hematopoietic cytokines including IL-3, only LTD4 significantly augmented the expansion of HPCs in a dose-dependent manner comparable to that of peptide growth factors. LTC4 and LTE4 were less effective. In CD34+ cell lines and primary HPCs, LTD4 induced phosphorylation of p44/42 ERK/MAPK and focal adhesion kinase-related tyrosine kinase Pyk2, which is linked to integrin activation. Bone marrow stromal cells produced biologically significant amounts of cysteinyl leukotrienes only when hematopoietic cells were absent, suggesting a regulatory feedback mechanism in the hematopoietic microenvironment. In contrast to antagonists of the homing-related G protein-coupled receptor CXCR4, administration of a CysLT1 antagonist failed to induce human CD34+ HPC mobilization in vivo. Our results suggest that cysteinyl leukotriene may contribute to HPC retention and proliferation only when cysteinyl leukotriene levels are increased either systemically during inflammation or locally during marrow aplasia. |
| Databáze: | OpenAIRE |
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