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Objective—Macrophages play a central role in the immune response against infectious organisms. Once activated, macrophages secrete proinflammatory cytokines and chemokines. Interleukin (IL)-8 and related CXC chemokines play a role in the recruitment and activation of phagocytes acting through CXCR1 and CXCR2 receptors. The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ exerts antiinflammatory properties in macrophages, by inhibiting cytokine and CC chemokine production. In this study, we investigated whether PPAR-γ also plays a role in the regulation of the CXC chemokine pathway.Methods and Results—Synthetic PPAR-γ ligands increase CXCR2 but not CXCR1 gene expression in a PPAR-γ-dependent manner in primary human macrophages in vitro and in atherosclerotic plaques in vivo. The increase of CXCR2 mRNA was paralleled by an increase in membrane protein expression. EMSA, ChIP, and transient transfection assays indicate that PPAR-γ activates the CXCR2 promoter by binding to a PPAR response element (PPRE). Finally, human macrophages acquire responsiveness to the CXCR2 ligands (IL-8 and Groβ), as measured by superoxide anion production, after induction of CXCR2 expression by PPAR-γ ligands.Conclusions—Our results provide a novel mechanism via which PPAR-γ can enhance the immune response in human macrophages. more...

Objective— The newly identified apolipoprotein A5 ( APOA5 ), selectively expressed in the liver, is a crucial determinant of plasma triglyceride levels. Because elevated plasma triglyceride concentrations constitute an independent risk factor for cardiovascular diseases, it is important to understand how the expression of this gene is regulated. In the present study, we identified the retinoic acid receptor-related orphan receptor-α (RORα) as a regulator of human APOA5 gene expression. Methods and Results— Using electromobility shift assays, we first demonstrated that RORα1 and RORα4 proteins can bind specifically to a direct repeat 1 site present at the position −272/−260 in the APOA5 gene promoter. In addition, using transient cotransfection experiments in HepG2 and HuH7 cells, we demonstrated that both RORα1 and RORα4 strongly increase APOA5 promoter transcriptional activity in a dose-dependent manner. Finally, adenoviral overexpression of hRORα in HepG2 cells led to enhanced hAPOA5 mRNA accumulation. We show that the homologous region in mouse apoa5 promoter is not functional. Moreover, we show that in staggerer mice, apoa5 gene is not affected by RORα. Conclusions— These findings identify RORα1 and RORα4 as transcriptional activators of human APOA5 gene expression. These data suggest an additional important physiological role for RORα in the regulation of genes involved in lipid homeostasis and probably in the development of atherosclerosis. more...