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The CysLT₁ Ligand Leukotriene D₄ Supports ₄β₁- and ₅β₁-Mediated Adhesion and Proliferation of CD34⁺ Hematopoietic Progenitor Cells¹

Andreas M. Boehmler^*, Adriana Drost^*, Lena Jaggy^*, Gabriele Seitz^*, Tina Wiesner^*, Claudio Denzlinger, Lothar Kanz^* and Robert Möhle^2,*

^* Department of Medicine II, University of Tübingen, Tübingen, Germany; and Department of Medicine III, Marienhospital, Stuttgart, Germany

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 ₄β₁ and ₅β₁ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 510/A4 and Deutsche José Carreras Leukämiestiftung Grants DJCLS R04/13 and R08/24v.

² Address correspondence and reprint requests to Dr. Robert Möhle, Department of Medicine II, University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. E-mail address: robert.moehle{at}med.uni-tuebingen.de

³ Abbreviations used in this paper: HPC, hematopoietic stem and progenitor cell; BMEC, bone marrow endothelial cell; CAFC, cobblestone area-forming cell; EIA, enzyme immunoassay; GPCR, G protein-coupled receptor; 5-LO, 5-lipoxygenase; LT, leukotriene; MPA, mycophenolic acid; PTX, pertussis toxin; rh, recombinant human; SDF, stromal cell-derived factor.