Regulation of expression of the human monocyte chemotactic protein-1 receptor (hCCR2) by cytokines

Abstract

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 γ inhibited MCP-1 binding by 60% at 48 h. The combination of macrophage colony- stimulating factor and interferon γ increased the inhibition to 80% at 48 h. This treatment has been shown previously to induce secretion of tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in monocytes. Incubation of THP-1 cells with TNF-α 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- α 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.