Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release.
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| Abstract |
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 PPARbeta/delta 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 PPARbeta/delta by its selective ligand GW501516 inhibits TNF-alpha-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-alpha-activated HUVECs were also inhibited markedly by GW501516. These inhibitory responses of GW501516 on activated endothelium were accompanied by a reduction in TNF-alpha-induced endothelial GRO-alpha release and VCAM-1, E-selectin, and ICAM-1 mRNA expression. Taken together, our results show that PPARbeta/delta modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.
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| Authors | Laura Piqueras, Maria Jesus Sanz, Mauro Perretti, Esteban Morcillo, Lucy Norling, Jane A Mitchell, Yoyo Li, David Bishop-Bailey |
| Journal | Journal of leukocyte biology (J Leukoc Biol) Vol. 86 Issue 1 Pg. 115-22 (Jul 2009) ISSN: 1938-3673 [Electronic] United States |
| PMID | 19389799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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