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1.
Arterioscler Thromb Vasc Biol ; 19(12): 2847-53, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10591660

ABSTRACT

Atherosclerosis can be viewed in part as an inflammatory disease process and may therefore be susceptible to manipulation of the immune state. Interleukin 10 (IL-10) is an inhibitory cytokine produced by activated lymphocytes and monocytes. These studies present evidence that IL-10 can inhibit minimally oxidized LDL (MM-LDL)-induced monocyte-endothelium interaction as well as inhibit atherosclerotic lesion formation in mice fed an atherosclerotic diet. Pretreatment of human aortic endothelial cells (HAECs) for 18, but not 4, hours with recombinant IL-10 caused a significant decrease in MM-LDL-induced monocyte binding. IL-10 was found to be maximally effective at 10 ng/mL. Transfection of HAECs with adenovirus expressing viral bcrf-1 IL-10 (Ad-vIL-10) in a sense but not antisense orientation completely inhibited the ability of MM-LDL to induce monocyte binding. Similar results were obtained with IL-10 or Ad-vIL-10 in HAECs stimulated with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). We have previously shown increases in cAMP associated with MM-LDL activation of endothelial cells. The MM-LDL-induced increase in cAMP levels was not inhibited by preincubation with IL-10. In vivo studies demonstrated that mice with a murine IL-10 transgene under the control of the human IL-2 promoter have decreased lesions versus controls on an atherogenic diet (5433+/-4008 mm(2) versus 13 574+/-4212 mm(2); P<0.05), whereas IL-10 null mice have increased lesions (33 250+/-9117 mm(2); P<0.0001) compared with either controls or IL-10 transgenic mice. These studies suggest an important role for IL-10 in the atherosclerotic disease process.


Subject(s)
Arteriosclerosis/drug therapy , Arteriosclerosis/immunology , Interleukin-10/immunology , Interleukin-10/pharmacology , Adenoviridae/genetics , Animals , Aorta/cytology , Arteriosclerosis/pathology , Cell Adhesion/drug effects , Cell Adhesion/immunology , Cells, Cultured , Disease Models, Animal , Endothelium, Vascular/cytology , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Gene Expression Regulation, Viral , Humans , In Vitro Techniques , Interleukin-10/genetics , Lipoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/immunology , Oxidation-Reduction , Phospholipid Ethers/pharmacology
2.
Proc Natl Acad Sci U S A ; 96(21): 12010-5, 1999 Oct 12.
Article in English | MEDLINE | ID: mdl-10518567

ABSTRACT

We previously have demonstrated that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL), activates endothelial cells to bind monocytes. 1-Palmitoyl-2- (5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC) and 1- palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate that these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyte-specific endothelial interactions. Treatment of endothelial cells with POVPC increased monocyte binding by inducing the surface expression of the connecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent pathway, resulting in down-regulation of NF-kappaB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence to suggest that the two phospholipids act by different novel receptors present in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide evidence that both POVPC and PGPC are important regulators of leukocyte-endothelial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.


Subject(s)
Endothelium, Vascular/physiology , Monocytes/physiology , Neutrophils/physiology , Phospholipid Ethers/pharmacology , Phospholipids/chemistry , Aorta/drug effects , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Survival , Cells, Cultured , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , E-Selectin/metabolism , Endothelium, Vascular/drug effects , Fibronectins/metabolism , Humans , Models, Biological , Monocytes/drug effects , Neutrophils/drug effects , RNA, Messenger/metabolism , Transfection , Up-Regulation , Vascular Cell Adhesion Molecule-1/metabolism
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