Modulation of CXCR4 expression and SDF-1alpha functional activity during differentiation of human monocytes and macrophages.
Chemoattraction of monocytes by the CXC chemokine stromal cell-derived factor-1alpha (SDF-1alpha) and its receptor CXCR4 may be involved in vascular diseases like atherosclerosis. We studied the regulation of CXCR4 transcription and SDF-1-induced functional responses in human monocytes during their differentiation in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), oxidized low-density lipoprotein (Ox-LDL), and unmodified LDL. Our results reveal that the rapid decline of SDF-1-mediated [Ca2+]i influx after monocyte isolation is followed by a gradual functional restoration and a concomitant reexpression of CXCR4 mRNA over time. A further three- to fourfold induction of CXCR4 mRNA occurred in macrophage-derived foam cells on treatment with Ox-LDL. HL-60 cells induced with phorbol myristate acetate (PMA) showed a rapid fourfold stimulation of CXCR4 mRNA within 1 h, declining to barely detectable levels at 3 h, with eventual restoration over time, mirroring the expression pattern in monocytes. Surface expression of CXCR4 is maintained in HL-60 cells during PMA-induced differentiation, as demonstrated by flow cytometry. GM-CSF had no effect on CXCR4 mRNA in HL-60 cells and does not cause its down-regulation in human macrophages.
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Shalley_K_Gupta@sbphrd.com
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D002454:Cell Differentiation; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000166:cytology*; D008934:Mitogens / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D020298:U937 Cells; D015854:Up-Regulation
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D008077:Lipoproteins, LDL; D008934:Mitogens; D019718:Receptors, CXCR4; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate