Peroxisome proliferator activated receptor γ agonists suppress TNFα-induced ICAM-1 expression by endothelial cells in a manner potentially dependent on inhibition of reactive oxygen species

In this study, we investigated the anti-inflammatory effect of various peroxisome proliferator activated receptor gamma (PPARγ) agonists (15-deoxy-Δ12,14-prostaglandin J2, troglitazone, rosiglitazone, ciglitazone) on human aortic endothelial cells. Pretreatment with PPARγ agonists abrogated tumor necrosis factor α (TNFα)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and subsequent monocytic adhesion by endothelial cells. Because reactive oxygen species (ROS) have been reported to play important roles in pro-inflammatory signal transduction, the involvement of ROS was investigated as a potential mechanism of anti-inflammatory effect of PPARγ ligands. Consistent with previous reports in other cell types, blockade of TNFα-induced ROS by treatment with N-acetylcysteine, diphenylene iodonium or NADPH oxidase 4 (NOX4) siRNA suppressed TNFα-induced ICAM-1 expression and subsequent monocytic adhesion, indicating that TNFα mediates pro-inflammatory signals via NOX4-dependent ROS generation in human endothelial cells. Finally, pretreatment with PPARγ agonists significantly suppressed TNFα-induced increases of intracellular ROS. Our results collectively suggest that PPARγ agonists might exert an anti-inflammatory effect on endothelial cells in a ROS-dependent manner.