The CysLT1 ligand leukotriene D4 supports alpha4beta1- and alpha5beta1-mediated adhesion and proliferation of CD34+ hematopoietic progenitor cells.
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 CysLT(1), 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 CysLT(1) ligand, LTD(4), rapidly and significantly up-regulated alpha(4)beta(1) and alpha(5)beta(1) integrin-dependent adhesion of both primitive and committed HPC. LTD(4)-triggered adhesion was inhibited by specific CysLT(1) antagonists. The effects of other CysLT(1) ligands were weak (LTC(4)) or absent (LTE(4)). In serum-free liquid cultures supplemented with various hematopoietic cytokines including IL-3, only LTD(4) significantly augmented the expansion of HPCs in a dose-dependent manner comparable to that of peptide growth factors. LTC(4) and LTE(4) were less effective. In CD34(+) cell lines and primary HPCs, LTD(4) 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 CysLT(1) 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.
Boehmler
Andreas M
AM
Department of Medicine II, University of Tübingen, Tübingen, Germany.
Drost
Adriana
A
Jaggy
Lena
L
Seitz
Gabriele
G
Wiesner
Tina
T
Denzlinger
Claudio
C
Kanz
Lothar
L
Möhle
Robert
R
D018952:Antigens, CD34; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D017998:Leukotriene D4 / Q000502:physiology*; D010766:Phosphorylation; D018077:Receptors, Leukotriene / Q000819:agonists*; D017154:Stromal Cells; D015854:Up-Regulation / Q000502:physiology
D018952:Antigens, CD34; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor