6533b862fe1ef96bd12c7787

RESEARCH PRODUCT

Activation of PPARβ/δ inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release

subject

description

Abstract Activation of the nuclear receptor PPARb/d inhibits acute inflammatory responses in vitro with human primary cells and in vivo by targeting the endothelial cell-leukocyte interaction. The infiltration of PMNs into tissues is a prominent feature in inflammation. The mechanism underlying PMN recruitment depends on the release of chemotactic mediators and CAM expression on endothelial cells. The nuclear receptor PPARβ/δ is widely expressed in many tissues, including the vascular endothelium; however, its role in acute inflammation remains unclear. Using intravital microscopy in the mouse cremasteric microcirculation, we have shown that activation of PPARβ/δ by its selective ligand GW501516 inhibits TNF-α-induced leukocyte rolling flux, adhesion, and emigration in a dose-dependant manner. Moreover, GW501516 reduced the expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in the cremasteric postcapillary venules. Similarly, rolling and adhesion of hPMNs under physiological flow on TNF-α-activated HUVECs were also inhibited markedly by GW501516. These inhibitory responses of GW501516 on activated endothelium were accompanied by a reduction in TNF-α-induced endothelial GRO-α release and VCAM-1, E-selectin, and ICAM-1 mRNA expression. Taken together, our results show that PPARβ/δ modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.