Modulation of Adhesion Molecule Expression by TNF-alpha in Human Coronary Artery Endothelial Cells: Insights into the Pathogenesis of Kawasaki Syndrome

Abstract

Background: Kawasaki syndrome (KS) is characterized by acute elevations of pro-inflammatory cytokines, matrix metalloproteinase 9 (MMP-9) and other factors related to vascular remodeling. The events leading to coronary artery damage in KS are unknown. Methods: Human coronary artery endothelial cells (HCAEC), treated with TNF-α or pre-treated with various concentrations of salicylic acid or TGF-β prior to stimulation with TNF-α were analyzed for gene and protein expression of adhesion molecules by RT-PCR and cell-based ELISA, respectively. Results: TNF-α up-regulated ICAM-1, E-selectin and MCP-1 gene and protein expression in a time- and dose-dependent manner via the NF-κB pathway, which could be inhibited by salicylic acid, but not TGF-β. By contrast, cultured HCAEC did not produce MMP-9 when induced with TNF-α. However, we did observe increase in MMP-9 enzyme levels in peripheral blood mononuclear cells from acute phase of KS patients compared to the convalescent phase when cultured in vitro, without any stimulation. Conclusions: The ability of HCAEC to express adhesion molecules and secrete MCP-1 upon exposure to TNF-α allows us to formulate a hypothesis for the pathogenesis of KS: namely, MCP-1 provides a gradient to attract immune cells to sites of inflammation, allowing these cells to attach to the endothelium and undergo extravasation into the extracellular matrix. Once there, the immune cells release enzymes that assists in vascular remodeling, thereby weakening the endothelium and hastening the process of aneurysm formation. In addition to preventing thrombosis and lowering fever in KS, salicylic acid may also function in down-regulating the expression of adhesion molecules during the inflammatory stage. [U.S. Public Health Service grant G12RR/AI-03061 from the RCMI Program, NCRR, NIH]