Involvement of leukotactin-1, a novel CC chemokine, in human atherosclerosis

Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, South Korea.
Atherosclerosis (Impact Factor: 3.99). 06/2004; 174(1):35-42. DOI: 10.1016/j.atherosclerosis.2003.11.024
Source: PubMed


Atherosclerosis is a chronic inflammatory disease that involves the recruitment of leukocytes to the arterial wall. Leukotactin-1 (Lkn-1), a new member of the CC chemokine family, is a potent chemoattractant for leukocytes and thus is implicated in inflammatory diseases. In this study, we investigated the possible association of Lkn-1 with human atherosclerosis. Atherosclerotic lesion and plasma samples were obtained from atherosclerotic patients. Human THP-1 monocyte-derived foam cells were prepared by treatment with an oxidized low-density lipoprotein. The expression level of Lkn-1 or its receptors mRNA was measured by RT-PCR analysis. Levels of plasma Lkn-1, MCP-1, ICAM-1 and total cholesterol were measured by ELISA or enzymatic assay. Lkn-1 expression was markedly enhanced not only at the mRNA level in human atherosclerotic lesions, but also at the circulating level in atherosclerosis patients compared with normal subjects. An in vitro study revealed that the level of Lkn-1 release was significantly enhanced by oxidative stress or proatherogenic mediators in macrophages and macrophage-derived foam cells. Lkn-1 stimulated endothelial cells to release ICAM-1, which is implicated in atherogenesis. Taken together, our data suggest that Lkn-1 plays an important role in the development of atherosclerosis.

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    • "* P < 0.05, significantly different from the control without Lkn-1/CCL15 treatment. phages and macrophage-derived foam cells (Yu et al., 2004). Therefore, it can be postulated that macrophages and macrophage-derived foam cells in atherosclerotic lesions may enhance the local concentration of Lkn-1 in the lesions, and Lkn-1/CCL15 subsequently stimulate the macrophages/foam cells per se to secrete MMP-9, indicating that Lkn-1/CCL15 action on macrophages and foam cells to release MMP-9 may contribute to plaque destabilization in the progression of atherosclerosis. "
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    ABSTRACT: Atherosclerosis is characterized by a chronic inflammatory disease, and chemokines play an important role in both initiation and progression of atherosclerosis development. Leukotactin-1 (Lkn-1/CCL15), a new member of the human CC chemokine family, is a potent chemoattractant for leukocytes. Our previous study has demonstrated that Lkn-1/CCL15 plays a role in the initiation of atherosclerosis, however, little is currently known whether Lkn-1/CCL15 is associated with the progression of atherosclerosis. Matrix metalloproteinases (MMPs) in human coronary atherosclerotic lesions play a crucial role in the progression of atherosclerosis by altering the vulnerability of plaque rupture. In the present study, we examined whether Lkn-1/CCL15 modulates MMP-9 release, which is a prevalent form expressed by activated macrophages and foam cells. Human THP-1 monocytic cells and/or human peripheral blood monocytes (PBMC) were treated with phorbol myristate acetate to induce their differentiation into macrophages. Foam cells were prepared by the treatment of THP-1 macrophages with human oxidized LDL. The macrophages and foam cells were treated with Lkn-1/CCL15, and the levels of MMP-9 release were measured by Gelatin Zymography. Lkn-1/CCL15 significantly enhanced the levels of MMP-9 protein secretion from THP-1 monocytic cells-derived macrophages, human PBMC-derived macrophages, as well as macrophage-derived foam cell in a dose dependent manner. Our data suggest that the action of Lkn-1/CCL15 on macrophages and foam cells to release MMP-9 may contribute to plaque destabilization in the progression of atherosclerosis.
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