intima. Here, they receive a series selleck bio of differentiation signals including macrophage col ony stimulating factor and minimally o idized LDL that enables them to mature into macrophages. These macrophages then engulf large quantities of cholesterol to become lipid laden foam cells. And it is the accumulation of these foam cells that eventually leads to the formation of characteristic fatty streaks, intermediate lesions and fibrous plaques. To date, though, the actual role of chemokines and their receptors in atherosclerosis has not been clearly estab lished. However, recent studies using transgenic mouse models of atherosclerosis have provided convincing evi dence that CCR2 is required for disease progression in apolipoprotein E null mice.

In these animals, dis ruption of the CCR2 gene greatly decreases lesion forma tion without affecting plasma lipid or lipoprotein concentrations. Using a slightly different approach Roll ins and colleagues have demonstrated that CCL2, the lig and for CCR2, plays an equally important role in the development of atherosclerosis in low density lipoprotein receptor deficient mice. Here, deletion of CCL2 leads to a significant reduction in lipid deposition within the aorta. Despite the promising e perimental results from these systems, relatively little is known about how the e pres sion of chemokine receptor genes is regulated in normal or diseased human tissues. A recent paper by Yamamoto and colleagues e amined the basal regulatory mech anisms underlying e pression of the CCR2 gene in the human monocyte cell line, THP 1.

Indeed, this group characterized two key elements that seemed to be neces sary and sufficient for the basal regulation of CCR2 e pression an Oct 1 binding sequence located 36 bp upstream of the TATA bo and a tandem CAAT enhancer binding protein binding sequence located, unu sually, in the 5 UTR. However, studies have not directly e amined the molecular mechanisms by which basal e pression of CCR2 is rapidly downregulated during the differentiation of monocytes into macro phages. In an effort to address this issue, we have further devel oped a model of monocyte differentiation using THP 1 cells, which can be induced to mature into macrophages using either phorbol esters and ionomycin or a physiolog ical combination of interferon and M CSF.

AV-951 In common with other studies, we report here that THP 1 cell maturation mediated by either high concentrations of PMA alone, or very low concentrations of PMA plus ionomycin is characterized by an increase in size, the development of an adherent pheno type new product and the up regulation of a panel of differentiation markers, in addition, CCR2, but not CCR1, was specifically down regulated during differentiation. Modu lation of CCR2 by PMA, but not PMA plus ionomycin, was found to be sensitive to inhi bition by the broad spectrum protein kinase inhibitor staurosporine. Furthermore, transient transfection of THP 1 cells with a CCR2 specific reporter construct indi cated that PM