Regulation of expression of the human monocyte chemotactic protein-1 receptor (hCCR2) by cytokines.
Monocytes enter the subendothelial space in response to a variety of chemotactic agents, notably including monocyte chemotactic protein-1 (MCP-1). To better understand the role of the human MCP-1 receptor (hCCR2) in monocyte recruitment, we have examined the effects of cytokines on expression of the receptor gene by ligand binding and Northern blot analysis. THP-1 cells expressed on average about 5000 MCP-1 receptors/cell. Differentiation of the cells induced by phorbol myristate acetate resulted in a 75% reduction of receptor gene expression within 2 h. Macrophage colony-stimulating factor had only moderate effect on hCCR2 expression. However, interferon gamma inhibited MCP-1 binding by 60% at 48 h. The combination of macrophage colony-stimulating factor and interferon gamma increased the inhibition to 80% at 48 h. This treatment has been shown previously to induce secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) in monocytes. Incubation of THP-1 cells with TNF-alpha and IL-1 induced a rapid down-regulation of hCCR2 expression and eventual loss of receptor protein. These cytokines exerted their regulatory role at the level of gene transcription. The effect of TNF-alpha alone persisted for 48 h, whereas the cells treated with IL-1 alone regained all of their receptor activity by 48 h. Our results suggest that cytokines can profoundly affect the expression of hCCR2 and thus modulate the recruitment of monocytes into sites of acute and chronic inflammation, including the developing atherosclerotic lesion.
Tangirala
R K
RK
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Murao
K
K
Quehenberger
O
O
D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009500:Neutralization Tests; D011485:Protein Binding; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C515334:CCR2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D013755:Tetradecanoylphorbol Acetate