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      Localisation of mRNA for JE/MCP-1 and Its Receptor CCR2 in Atherosclerotic Lesions of the ApoE Knockout Mouse


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          MCP-1 has potent chemotactic activity for monocytes and is strongly implicated in the pathogenesis of atherosclerosis. In the present study, we have used in situ hybridisation to examine the gene expression of JE, the murine homologue of MCP-1, and its receptor, CCR2, during the development of atherosclerotic lesions in the ApoE knockout mouse. Interestingly, the earliest expression of JE detected during lesion development was found to be localised in mesenchymal cells in the adventitia and not in the intima. Macrophages were subsequently found to accumulate in these affected regions of the adventitia and these cells were found to express high levels of JE. At this stage, early macrophage-rich lesions with high expression of JE were also seen in the intima, but expression of mRNA for the receptor for JE (CCR2) was only found on adventitial macrophages and not in the intima. This sequence of events suggests that adventitial inflammation may be an important early event in lesion development and responsible for the subsequent accumulation of macrophages in the intima possibly by recruitment from the adventitia as well as via the vessel lumen.

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          Molecular cloning of gene sequences regulated by platelet-derived growth factor.

          We have screened a cDNA library for gene sequences that are regulated by platelet-derived growth factor (PDGF) in BALB/c-3T3 cells. Of 8000 clones screened, less than 14 independent PDGF-inducible sequences were found. Two of these (KC and JE) were studied in detail. By hybrid-selection and translation the KC and JE mRNAs encode 10,000 and 19,000 dalton polypeptides, respectively. In the absence of PDGF, the JE and KC sequences correspond to low abundance mRNAs. One hour after addition of PDGF their abundance level can be increased 10- to 20-fold. Within 4 hr, a 60-fold induction of JE can be attained. Nanogram per ml quantities of pure PDGF regulate these sequences whereas microgram/ml quantities of chemically unrelated mitogens (EGF, insulin, or platelet-poor plasma) have either a weak or an undetectable effect. Inhibitors of protein synthesis block the progression of quiescent 3T3 cells through G1 into S phase; however these drugs do not block the induction of KC and JE by PDGF. This result indicates that these sequences correspond to "early genes" which are not induced as a consequence of cell growth, but rather are directly regulated by PDGF.
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            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.
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              Chemokines and atherosclerosis.

              The recruitment of mononuclear leukocytes, and the migration, growth and activation of macrophages, lymphocytes and smooth muscle cells within lesions, are critical features of the chronic inflammatory response that typifies atherogenesis. Chemokines are members of a superfamily of small polypeptides that mediate not only migration, but also growth and activation of leukocytes and a variety of other cells. Monocyte chemoattractant and activating protein-1 was the first chemokine to be implicated in leukocyte-mediated inflammation in atherosclerosis. This review emphasizes new information on the potential atherogenic roles of monocyte chemoattractant and activating protein-1 and several other closely related chemokines of the C-C subfamily. We focus particular attention on the newly recognized atherogenic role of a subgroup of closely related chemokines of the C-X-C subfamily that includes interleukin-8 and growth regulated oncogene alpha. We also discuss new studies that reveal how CD40 ligand and certain other stimuli can promote chemokine expression in atherosclerosis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2000
                31 March 2000
                : 37
                : 2
                : 93-102
                Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park North, Harlow, UK
                25720 J Vasc Res 2000;37:93–102
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 31, Pages: 10
                Research Paper


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