Atherosclerosis is characterized by a complex immune response in the vessel wall, involving both inflammation and autoimmune processes. EpsteinBarr virus-induced gene 3 (Ebi3) is a member of the interleukin (IL)-12 heterodimeric cytokine family, which has important immunomodulatory functions. To date, little is known about the role of Ebi3 in vascular disease. We examined the expression of Ebi3 in human atheromatous lesions and analyzed its transcriptional regulation in vascular cells. The in situ expression of Ebi3 in human endarterectomy specimens was analyzed by immunohistochemistry. In these lesions, smooth muscle cells expressed Ebi3 as well as the IL-27␣/p28 and IL-12␣/p35 subunits. Primary aortic smooth muscle cells up-regulated Ebi3 in response to proinflammatory stimuli like tumor necrosis factor-␣ and interferon-␥. Interestingly , pretreatment of these cells with the peroxisome proliferator-activated receptor-␥ agonist rosiglitazone strongly reduced Ebi3 induction. Chromatin immunoprecipitation experiments revealed that this inhibition is due to interference with p65/RelA recruitment to the Ebi3 promoter. Our data support a possible role of Ebi3 in atherogenesis either as homodimer or as IL-27/IL-35 heterodimer, and suggest that Ebi3 could be an interesting target for therapeutic manipulation in atherosclerosis.
Introduction: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering GLP-1(7-36) to the metabolically inactive GLP-1(9-36), are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis.
The clusters Ti(6)O(4)(OPr)(8)(OOC(CH(2))(2)C[triple bond]CH)(8) and [Zr(6)O(4)(OH)(4)(OOC(CH(2))(3)C[triple bond]CH)(12)](2) with acetylenic carboxylate ligands were prepared and structurally characterized in solution and in the crystalline state. Model reactions showed that they are suitable candidates for the formation of cluster-based inorganic-organic hybrid materials by alkyne-azide click reactions.
Abstract-Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis.Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-␥-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPAR␥ in this context. CD4-positive lymphocytes express both the AT1R and PPAR␥. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1Ϯ3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6Ϯ0.7-fold induction at 10 mol/L of telmisartan (PϽ0.01 compared with SDF-1-treated cells; nϭ22). Three different PPAR␥ activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPAR␥-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPAR␥ small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPAR␥. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPAR␥-activating properties. Key Words: telmisartan Ⅲ PPAR␥ Ⅲ angiotensin type 1 receptor blocker Ⅲ CD4-positive lymphocytes Ⅲ migration A therogenesis is an inflammatory process in the vessel wall involving inflammatory cells like monocytes, macrophages, and CD4-positive lymphocytes. 1 In early atherogenesis, CD4-positive lymphocytes are attracted by chemotactic proteins, such as regulated upon activation, normal T-cell expressed, and secreted (RANTES) and stromal cellderived factor (SDF)-1 and enter the vessel wall as naïve T-helper 0 cells. In the subendothelium, these cells then encounter antigens like oxidized low-density lipoprotein and differentiate into T-helper 1 cells, subsequently releasing proinflammatory mediators like tumor necrosis factor-␣ and interferon-␥. These cytokines then govern the inflammatory response in the vessel wall by activating other cells, such as endothelial cells, macrophages, and vascular smooth muscle cells, thus promoting the inflammatory process in atherogenesis. It is unclear whether an inhibition of cell migration itself modulates vascular disease, but various experimental studies have shown that a reduction in CD4-positive lymphocyte recruitment hampers lesion development and plaque formation. 2,3 Still, most of these studies targeted the effect of T-cell-specific chemokines, but hitherto little is known about modulatory effects on CD4-positive lymphocyte migration.T...
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