title: Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release.
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.
authors.affiliation: Fundacion Hospital Clinico Universitario de Valencia, Universidad de Valencia, Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Piqueras
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.forename: Lucy
authors.initials: L
authors.lastname: Norling
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: Yoyo
authors.initials: Y
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D018925:Chemokines / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D015870:Gene Expression; D007249:Inflammation / Q000276:immunology; D036904:Leukocyte Rolling; D051379:Mice; D008833:Microcirculation / Q000276:immunology; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply; D047494:PPAR delta / Q000819:agonists / Q000502:physiology*; D048068:PPAR-beta / Q000819:agonists / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D047494:PPAR delta; D048068:PPAR-beta; D014409:Tumor Necrosis Factor-alpha