Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

Background: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPAR alpha and delta activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPAR alpha and delta agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells. Results: We found that PPAR alpha and PPAR delta agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPAR delta induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPAR alpha failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPAR delta, but not PPAR alpha agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPAR alpha and PPAR delta agonists increased ICAM-1 mRNA stability. Conclusion: Therefore, our data provide the first evidence that PPAR alpha and PPAR delta agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.