The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

Objective-Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD). Methods and Results-We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the CX3CR1 ϩ CD3 ϩ CD8 ϩ T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments. Key Words: atherosclerosis Ⅲ coronary artery disease Ⅲ cytokines Ⅲ immune system Ⅲ leukocytes B esides lipid deposition and vascular smooth muscle cell (VSMC) proliferation, the infiltration of monocytes and T cells is a cardinal feature of atherosclerotic plaques of all stages. 1,2 This persistent recruitment of mononuclear cells into the vessel wall is a critical step in atherogenesis, and growing evidence suggests that chemokines are involved in these processes by activating and directing leukocytes into atherosclerotic lesions. 3,4 Fractalkine (CX3CL1) is the unique member of the CX3C chemokine subfamily. In contrast to other chemokines, it exists in two forms, each mediating distinct biological actions. 5 The membrane-anchored protein, which is expressed primarily on the inflamed endothelium, serves as an adhesion protein promoting the retention of monocytes and T cells. 6 The soluble form resembles more a conventional chemokine and strongly induces chemotaxis. Both chemotaxis and adhesion are mediated by the G protein-coupled receptor CX3CR1. 7,8 Based on these chemotactic and adhesive properties, CX3CL1 has been suggested to play an important role in inflammation and accumulating evidence indicates that CX3CL1/CX3CR1 are involved in the pathogenesis of various inflammatory disorders. 9,10 Recently, two independent reports showed that the targeted deletion of CX3CR1 decreased atherosclerosis in mice, implicating a role of this chemokine system in atherogenesis. 11,12 Moreover, Lucas et al and Greaves et al have recently shown expression of CX3CL1 and CX3CR1 in human coronary atherosclerotic plaques, 13,14 ...

Background-Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins). Methods and Results-In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1␤ was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1␤ and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1␣ and IL-1␤ were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, nϭ15) and atorvastatin (80 mg/d, nϭ15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1␤ and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1␣, IL-1␤, and IL-1Ra were increased in PBMCs from patients with stable (nϭ20) and unstable (nϭ20) angina compared with healthy control subjects (nϭ15). Although the unstable patients had particularly high levels of IL-1␤ and IL-1␣, IL-1Ra was not correspondingly increased. (3) IL-1␤ induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect. Conclusions-Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.