Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release.
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.
Piqueras
Laura
L
Fundacion Hospital Clinico Universitario de Valencia, Universidad de Valencia, Valencia, Spain.
Sanz
Maria Jesus
MJ
Perretti
Mauro
M
Morcillo
Esteban
E
Norling
Lucy
L
Mitchell
Jane A
JA
Li
Yoyo
Y
Bishop-Bailey
David
D
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
D015815:Cell Adhesion Molecules; D018925:Chemokines; D047494:PPAR delta; D048068:PPAR-beta; D014409:Tumor Necrosis Factor-alpha