Peroxisome-proliferator-activated receptor gamma (PPARgamma) is required for modulating endothelial inflammatory response through a nongenomic mechanism.
Besides their well-known anti-diabetic effects, the peroxisome-proliferator-activated receptor gamma (PPARgamma) thiazolidinedione ligands (TZD) have been suggested to also display anti-inflammatory properties. The receptor role in mediating such effects is far from being elucidated. Here, we demonstrated that PPARgamma is necessary for TZD to interfere with TNFalpha and IFNgamma inflammatory activity in human endothelial cells. Different PPARgamma ligands similarly inhibit cytokinic stimulation of IFNgamma-inducible-protein-of-10-kDa (IP10) secretion in a dose-dependent manner and prevent the induced phosphorylation/activation of extracellular-signaling-regulated-kinases (ERK1/2). To further confirm the PPARgamma role in mediating both rapid and long term anti-inflammatory effects of its ligands, we evaluated RGZ inhibitory action in PPARgamma-silenced and -overexpressing cells. PPARgamma-silencing results in a reversion of RGZ inhibitory activity on cyto/chemokine secretions and rapid ERK phosphorylation. Conversely, receptor overexpression significantly increases RGZ inhibitory activity. Finally, PPARgamma-overexpression results in a reduction of ERK1/2 phosphorylation and inflammatory secretions in response to TNFalpha and IFNgamma even in the absence of RGZ, suggesting a restraining effect controlled by endogenous ligands. In conclusion, our data provide the first evidence that PPARgamma is involved in the anti-inflammatory action of TZD in endothelial cells, not only by modulating cyto/chemokine secretions but also by restraining ERK activation through a novel rapid nongenomic mechanism.
DENOthe Center of Excellence for Research, Transfer and High Education, University of Florence, Florence, Italy.
Giulia
G
Cantini
Adriana
A
Lombardi
Elisa
E
Borgogni
Michela
M
Francalanci
Elisabetta
E
Ceni
Selene
S
Degl'Innocenti
Stefania
S
Gelmini
Giada
G
Poli
Andrea
A
Galli
Mario
M
Serio
Gianni
G
Forti
Michaela
M
Luconi
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
D047495:PPAR gamma; D045162:Thiazolidinediones