Peroxisome Proliferator-Activated Receptor-γ Activators Inhibit IFN-γ-Induced Expression of the T Cell-Active CXC Chemokines IP-10, Mig, and I-TAC in Human Endothelial Cells

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Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear hormone receptor superfamily originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate inflammatory responses. Given the importance of endothelial cell (EC)-derived chemokines in regulating leukocyte function and trafficking, we studied the effects of PPARγ ligands on the expression of chemokines induced in ECs by the Th1 cytokine IFN-γ. Treatment of ECs with PPARγ activators significantly inhibited IFN-γ-induced mRNA and protein expression of the CXC chemokines IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T-cell α-chemoattractant (I-TAC), whereas expression of the CC chemokine monocyte chemoattractant protein-1 was not altered. PPARγ activators decreased IFN-inducible protein of 10 kDa promoter activity and inhibited protein binding to the two NF-κB sites but not to the IFN-stimulated response element ISRE site. Furthermore, PPARγ ligands inhibited the release of chemotactic activity for CXC chemokine receptor 3 (CXCR3)-transfected lymphocytes from IFN-γ-stimulated ECs. These data suggest that anti-diabetic PPARγ activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation.