Abstract
Interleukin-4 (IL-4)-mediated pro-oxidative and pro-inflammatory vascular environments have been implicated in the pathogenesis of atherosclerosis. The cellular and molecular regulatory mechanisms underlying this process, however, are not fully understood. In the present study, we employed GeneChip microarray analysis to investigate global gene expression patterns in human vascular endothelial cells after treatment with IL-4. Our results showed that mRNA levels of a total of 106 genes were significantly up-regulated and 41 genes significantly down-regulated with more than a 2-fold change. The majority of these genes are critically involved in the regulation of inflammatory responses, apoptosis, signal transduction, transcription factors, and metabolism; functions of the remaining genes are unknown. The changes in gene expression of selected genes related to inflammatory reactions, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6), were verified by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. IL-4 treatment also significantly increased the adherence of inflammatory cells to endothelial cell monolayers in a dose-dependent manner. These results may help determine the molecular mechanisms of action of IL-4 in human vascular endothelium. In addition, a better understanding of IL-4-induced vascular injury at the level of gene expression could lead to the identification of new therapeutic strategies for atherosclerosis.
Highlights
Inflammatory responses elicited by a variety of stimuli in the vascular endothelium have been implicated in the development of cardiovascular disease
IL-4 Up-regulates Adhesion of Leukocytes to Human Vascular Endothelial Cell Monolayers The adherence of human acute monocytic leukemia cells, THP-1, to Human umbilical vein endothelial cells (HUVEC) monolayers was determined to verify the functional integrity of inflammatory mediators up-regulated by human vascular endothelial cells after stimulation with IL-4
Identification of Global Gene Expression Changes in IL-4–Treated Human Vascular Endothelial Cells The gene expression profile of human vascular endothelial cells treated with IL-4 was assessed using microarray technology with the Affymetrix GeneChip Human Genome U133A Arrays, which contain more than 22000 human genes
Summary
Inflammatory responses elicited by a variety of stimuli in the vascular endothelium have been implicated in the development of cardiovascular disease. Enhanced expressions of adhesion molecules, chemokines, and pro-inflammatory cytokines in vascular endothelial cells facilitate recruiting and adhering of inflammatory cells, such as lymphocytes and monocytes/macrophages, into the vessel wall, and stimulate transendothelial migration, which can be considered an early atherogenic process [2,3,4,5]. These studies strongly support the idea that an inflammatory environment in the vascular endothelium is critical for the initiation and development of atherosclerosis. A growing body of evidence indicates that IL-4 may play a role in atherogenesis through induction of inflammatory responses, such as up-regulation of vascular cell adhesion molecule-1
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