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a Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA;
b Canadian Blood Services, Edmonton, Alberta, Canada;
c Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;
d James Graham Brown Cancer Center, Louisville, KY, USA
Key Words. Chemokines • Lymphocytes • Apoptosis • Cellular proliferation • Protein kinases
Mariusz Z. Ratajczak, M.D., Ph.D., Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, University of Pennsylvania, 405A Stellar Chance Labs, 422 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. Telephone: 215-573-3434; Fax: 215-573-6317; e-mail: mariusz{at}mail.med.upenn.edu
To better define the role HIV-related chemokine receptor-chemokine axes play in human hematopoiesis, we investigated the function of the CXCR4 and CCR5 receptors in human myeloid, T- and B-lymphoid cell lines selected for the expression of these receptors (CXCR4+, CXCR4+ CCR5+, and CCR5+ cell lines). We evaluated the phosphorylation of MAPK p42/44, AKT, and STAT proteins and examined the ability of the ligands for these receptors (stromal-derived factor-1 [SDF-1] and macrophage inflammatory protein-1ß [MIP-1ß]) to influence cell growth, apoptosis, adhesion, and production of vascular endothelial growth factors (VEGF), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in these cell lines. We found that A) SDF-1, after binding to CXCR4, activates multiple signaling pathways and that in comparison with the MIP-1ß-CCR5 axis, plays a privileged role in hematopoiesis; B) SDF-1 activation of the MAPK p42/44 pathway and the PI-3K-AKT axis does not affect proliferation and apoptosis but modulates integrin-mediated adhesion to fibronectin, and C) SDF-1 induces secretion of VEGF, but not of MMPs or TIMPs. Thus the role of SDF-1 relates primarily to the interaction of lymphohematopoietic cells with their microenvironment and does not directly influence their proliferation or survival. We conclude that perturbation of the SDF-1-CXCR4 axis during HIV infection may affect interactions of hematopoietic cells with the hematopoietic microenvironment.
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