Activation of PPARβ/δ 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.

Peroxisome Proliferator-activated Receptor δ Activators Induce IL-8 Expression in Nonstimulated Endothelial Cells in a Transcriptional and Posttranscriptional Manner*

“…Similar results were demonstrated by Fan et al, revealing that the PPAR␦ agonist GW501516 suppresses IL-1␤-induced VCAM-1 and E-selectin expression in human umbilical vein endothelial cells (HUVECs) (8). Piqueras et al demonstrated that PPAR␦ inhibits leukocyte recruitment and cell adhesion molecule expression (9). Recently, Liang et al showed that the PPAR␦ agonist L-165041 suppresses C-reactive protein-induced IL-6 expression (10).…”

Endothelium-Dependent Vasodilator Effects of Peroxisome Proliferator-Activated Receptor β Agonists via the Phosphatidyl-Inositol-3 Kinase-Akt Pathway

“…It has been recently described that PPAR-␤ localization is not restricted to the nucleus (Kelly et al, 2004). In addition, it is known that these receptors are present in VSMC and in endothelial cells (Kliewer et al, 1994;Piqueras et al, 2009). We found that the maximal vasodilator response to every agonist concentration was reached within 15 min, which suggests that it is independent of nuclear processes because it is not enough time for gene transcription.…”

The PPAR-RXR Transcriptional Complex in the Vasculature

“…60,67,68 In ECs, PPAR␦ activation reportedly limits adhesion molecule expression through various mechanisms, including protection against oxidative stress, inducing expression of target genes like thioredoxin and catalase. 69,70 Interestingly, decreasing PPAR␦ expression increased the effects seen, reminiscent of the BCL6 effects discussed earlier.…”

“…20,165 PPAR␦ limits endothelial inflammation, is activated by COX2 metabolism of endocannabinoids, and may play a part in reducing endothelial glucose uptake. 69,70,71,166 In VSMCs, both PPAR␣ and -␥ can limit cellular proliferation through mechanisms that include changes in telomerase activity. 23,[167][168][169] Alkanoic acids derived from urea may activate PPAR␣ in VSMC.…”