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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:932.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

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

Elena Rigamonti; Coralie Fontaine; Bruno Lefebvre; Christian Duhem; Philippe Lefebvre; Nikolaus Marx; Bart Staels; Giulia Chinetti-Gbaguidi

From the Institut Pasteur de Lille (E.R., C.F., B.L., C.D., P.L., B.S., G.C.-G.), Lille, F-59019 France; Inserm (E.R., C.F., B.L., C.D., P.L., B.S., G.C.-G.), U545, Lille, France; Université de Lille 2 (E.R., C.F., B.L., C.D., P.L., B.S., G.C.-G.), Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille, France; and the Department of Internal Medicine II (N.M), Cardiology, University of Ulm, Germany.

Correspondence to Bart Staels, Inserm UR 545, Institut Pasteur de Lille, 1, rue du Professeur Calmette, BP 245, Lille 59019, France. E-mail bart.staels{at}pasteur-lille.fr

Abstract

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) exerts antiinflammatory properties in macrophages, by inhibiting cytokine and CC chemokine production. In this study, we investigated whether PPAR- also plays a role in the regulation of the CXC chemokine pathway.

Methods and Results— Synthetic PPAR- ligands increase CXCR2 but not CXCR1 gene expression in a PPAR--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- 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- ligands.

Conclusions— Our results provide a novel mechanism via which PPAR- can enhance the immune response in human macrophages.

IL-8 recruits and activates phagocytes acting through CXCR1 and CXCR2 receptors. Regulation of these genes by PPAR- was studied in macrophages. PPAR- induces CXCR2 expression, leading to an acquired induction of ROS production in response to IL-8 and Groβ. These results provide a novel role for PPAR- in macrophage immune response.

Key Words: nuclear receptors • chemokines • gene regulation • immune response • macrophage