Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction

An early event in acute and chronic inflammation and associated diseases su ch as atherosclerosis and rheumatoid arthritis is the induced expression of specific adhesion molecules on the surface of endothelial cells (ECs), whi ch subsequently bind leukocytes. Peroxisome proliferator-activated receptor s (PPARs), members of the nuclear receptor superfamily of transcription fac tors, an activated by fatty acid metabolites, peroxisome proliferators, and thiazolidinediones and are now recognized as important mediators in the in flammatory response. Whether PAR activators influence the inflammatory resp onses of ECs is unknown. We show that the PPAR activators 15-deoxy-Delta(12 ,14)-prostaglandin J(2) (15d-PGJ(2)), Wyeth 14643, ciglitazone, and troglit azone, but not BRL 49653, partially inhibit the induced expression of vascu lar cell adhesion molecule-1 (VCAM-1), as measured by ELISA, and monocyte b inding to human aortic endothelial cells (HAECs) activated by phorbol 12-my ristate 13-acetate (PMA) or lipopolysaccharide. The "natural" PPAR activato r 15d-PGJ(2) had the greatest potency and was the only tested molecule capa ble of partially inhibiting the induced expression of E-selectin and neutro phil-like HL60 cell binding to PMA-activated HAECs. Intracellular adhesion molecule-1 induction by PMA was unaffected by any of the molecules tested. Both PPAR-alpha and PPAR-gamma mRNAs were detected in HAECs by using revers e transcription-polymerase chain reaction and a ribonuclease protection ass ay; however, we have yet to determine which, if any, of the PPARs are media ting this process. These results suggest that certain PPAR activators may h elp limit chronic inflammation mediated by VCAM-1 and monocytes without aff ecting acute inflammation mediated by E-selectin and neutrophil binding.