Accuri C6 Flow Cytometer System
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Published online before print April 23, 2009
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0508284

Received for publication May 7, 2008.
Revised February 25, 2009.
Accepted for publication March 3, 2009.

Article

Activation of PPAR{beta}/{delta} inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release

Laura Piqueras *{dagger}, Maria Jesus Sanz {ddagger}{sect}, Mauro Perretti {dagger}, Esteban Morcillo *{ddagger}{sect}, Lucy Norling {dagger}, Jane A. Mitchell ||, Yoyo Li {dagger}, and David Bishop-Bailey {dagger}@

*Fundacion Hospital Clinico Universitario de Valencia and{ddagger}Department of Pharmacology, Faculty of Medicine, Universidad de Valencia, Valencia, Spain;{sect}Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CIBERES), Valencia, Spain;{dagger}William Harvey Research, Barts and the London School of Medicine and Dentistry, London, United Kingdom; and||Cardiac Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom

@ To whom correspondence should be addressed. E-mail: d.bishop-bailey{at}qmul.ac.uk.


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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 PPAR{beta}/{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 PPAR{beta}/{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 PPAR{beta}/{delta} modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.

Key Words: vascular endothelium • neutrophils




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