Molecular Regulatory Mechanisms of IL-4-Induced MCP-1 Expression in Vascular Endothelium

The recruitment of inflammatory cells such as monocytes/macrophages and their migration throughout the vascular endothelium are thought to be critical early pathological events in atherogenesis. Evidence indicates that monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in this process. In facts, both MCP- mRNA and protein expression have been detected in early atherosclerotic lesions. In addition, it was demonstrated that MCP-1 deficiency significantly reduced atherosclerosis in low density lipoprotein (LDL) receptordeficient mice fed a high cholesterol diet. Recently, we reported that exposure of human vascular endothelial cells to interleukin-4 (IL-4) increases the intracellular oxidative stress and upregulates inflammatory mediators, such as vascular cell adhesion molecule-1 (VCAM-1) and MCP-1, which, in turn, can create the prooxidative and proinflammatory environments within the vascular endothelium. Based on our preliminary data, we hypothesize that IL-4 may trigger the transcription factor STAT1- mediated molecular signaling pathways leading to an enhanced MCP-1 expression via antioxidant-sensitive mechanisms in vascular endothelium. To test this hypothesis, we will investigate the effect of antioxidants, such as superoxide dismutase (SOD) and catalase,on the MCP-1 gene transcription and protein expression in IL-4-stimulated human endothelial cells. The transendothelial migration assays will also be performed to determine if antioxidants can attenuate the function of MCP-1, secreted from IL-4-treated endothelial cells, to chemoattract monocytes/macrophages. In addition, SOD-overexpressing endothelial cells and transgenic SOD-overexpressing mice will be employed to further elucidate the role of cellular antioxidants on IL-4-induced MCP-1 expression. Moreover, the proposed project will focus on the effect of antioxidants on the activation of STAT1 in IL-4-stimulated vascular endothelium to clarify molecular signaling pathways in the redox-regulated mechanisms of IL-4-induced MCP-1 expression. These studies may have implications for the elucidation of cellular and molecular signaling mechanisms involved in IL-4-mediated progression of atherosclerosis. Therefore, data arising from the proposed research project may contribute to a clinical strategy for the prevention and/or treatment of atherosclerotic lesion development specifically targeted against MCP-1 expression.