Pioglitazone Inhibits Dendritic Cell Adhesion And Transmigration Through Down-regulation Of DC-SIGN

Objective Atherosclerotic cardiovascular disease is the main cause of death, which begins as an inflammatory immunological reaction. Dendritic cells (DCs) are professional antigen presenting cells (APCs) which make an essential function in immune reactions. DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is a novel DC-specific adhesion receptor that takes part in the interaction between DCs and T cells or vascular endothelial cells (ECs). Pioglitazone (Pio) is one of the peroxisome proliferator activated receptors (PPARs), which are key regulators of glucose and fat metabolism. It has been confirmed to reduce cardiovascular events in patients with type 2 diabetes. The purpose of this study is to investigate the effect of Pio on DC-SIGN expression in cultured DC and explore the possible mechanism of Pio preventing atherogenesis through inhibition of DC adhesion and transmigration.Methods DC derived from human peripheral blood monouclear cells and human umbilical vein endothelial cells (HUVECs) were cultured in vitro. DC were treated with different concentration of Pio (0.1 μmol/L, 1.0 μmol/L, 10 μmol/L) in the presence or absence of peroxisome protiferator activated receptor-gamma (PPAR-γ) antagonist GW9662 (10 μmol/L) for 24 hours. DC-SIGN protein expression in cultured DC was analyzed by western blot assay or immunofluorescence test. And DC adhesion and transmigration were detected by adhesion assay and transmigration assay, respectively.Results DC-SIGN protein expression in cultured DC was significantly down-regulated by Pio in a concentration-dependent fashion, markedly decreased from 1.0μmol/L (both P<0.05 by western blot assay and immunofluorescence test)to 10 μmol/L (P<0.01 by western blot assay or P<0.001 by immunofluorescence test), and this effect could be reversed by GW9662 (P<0.05 by western blot assay or P<0.01 by immunofluorescence test). The adhesion and transmigration of DC were significantly inhibited by Pio in a concentration-dependent pattern, markedly degraded from 1.0 μmol/L (both P<0.05 in adhesion and transmigration) to 10 μmol/L (P<0.001 in adhesion or P<0.01 in transmigration), while this effect could be reversed by GW9662 (P<0.001 in adhesion or P<0.05 in transmigration). In addition, DC adhesion and transmigration were also obviously degraded by treatment of DC with anti-DC-SIGN antibody (P<0.001 in adhesion or P<0.01 in transmigration).Conclusions Pio may down-regulate DC-SIGN protein expression and inhibit DC adhesion and transmigration through the pathway of PPAR-γ, which indicates a novel pathophysiological mechanism for Pio to prevent atherogenesis.