Inhibition of immature erythroid progenitor cell proliferation by macrophage inflammatory protein-1alpha by interacting mainly with a C-C chemokine receptor, CCR1.
Several lines of evidence indicate that macrophage inflammatory protein-1alpha (MIP-1alpha) modulates the proliferation of hematopoietic progenitor cells, depending on their maturational stages. To clarify the mechanisms for the modulation of hematopoiesis by this chemokine, we examined the expression of a receptor for MIP-1alpha, CCR1, on bone marrow cells of normal individuals using a specific antibody and explored the effects of MIP-1alpha on in vitro erythropoiesis driven by stem cell factor (SCF) and erythropoietin (Epo). CCR1 was expressed on glycophorin A-positive erythroblasts in addition to lymphocytes and granulocytes. CCR1+ cells, isolated from bone marrow mononuclear cells (BMMNCs) using a cell sorter, comprised virtually all erythroid progenitor cells in the BMMNCs. Moreover, MIP-1alpha inhibited, in a dose-dependent manner, colony formation by burst-forming unit-erythroid (BFU-E), but not by colony forming unit-erythroid (CFU-E), in a methylcellulose culture of purified human CD34+ bone marrow cells. Although reverse-transcription polymerase chain reaction (RT-PCR) showed the presence of CCR1, CCR4, and CCR5 transcripts in CD34+ cells in BM, anti-CCR1 antibodies significantly abrogated the inhibitory effects of MIP-1alpha on BFU-E formation both in a methylcellulose culture and in a single cell proliferation assay of purified CD34+ cells. Although the contribution of CCR4 or CCR5 cannot be completely excluded, these results suggest that MIP-1alpha-mediated suppression of the proliferation of immature, but not mature erythroid progenitor cells, is largely mediated by CCR1 expressed on these progenitor cells.
Su
S
S
Department of Pharmacology, Cancer Research Institute, School of Medicine, Kanazawa University, Japan.
Mukaida
N
N
Wang
J
J
Zhang
Y
Y
Takami
A
A
Nakao
S
S
Matsushima
K
K
D000704:Analysis of Variance; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D004921:Erythropoietin / Q000494:pharmacology*; D006021:Glycophorins / Q000032:analysis / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*
D018952:Antigens, CD34; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017931:DNA Primers; D006021:Glycophorins; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D004921:Erythropoietin