Induction of CXCR2 Receptor by Peroxisome Proliferator-Activated Receptor γ in Human Macrophages

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.