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 c hemotactic agents, notably including monocyte chemotactic protein-1 (M OP-1). To better understand the role of the human MCP-1 receptor (hCCR S) in monocyte recruitment, we have examined the effects of cytokines on expression of the receptor gene by ligand binding and Northern blot analysis. THP-I cells expressed on average about 5000 MCP-I receptors /cell. Differentiation of the cells induced by phorbol myristate aceta te resulted in a 75% reduction of receptor gene expression within 2 h. Macrophage colony-stimulating factor had only moderate effect on hCCR S 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 treatme nt has been shown previously to induce secretion of tumor necrosis fac tor alpha (TNF-alpha) and interleukin 1 (IL-1) in monocytes. Incubatio n of THP-1 cells with TNF-alpha and IL-1 induced a rapid downregulatio n of hCCRS expression and eventual loss of receptor protein. These cyt okines exerted their regulatory role at the level of gene transcriptio n. 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 expre ssion of hCCRS and thus modulate the recruitment of monocytes into sit es of acute and chronic inflammation, including the developing atheros clerotic lesion.