Induction of CXCR2 receptor by peroxisome proliferator-activated receptor gamma 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) gamma exerts antiinflammatory properties in macrophages, by inhibiting cytokine and CC chemokine production. In this study, we investigated whether PPAR-gamma also plays a role in the regulation of the CXC chemokine pathway.


RESULTS
Synthetic PPAR-gamma ligands increase CXCR2 but not CXCR1 gene expression in a PPAR-gamma-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-gamma activates the CXCR2 promoter by binding to a PPAR response element (PPRE). Finally, human macrophages acquire responsiveness to the CXCR2 ligands (IL-8 and Grobeta), as measured by superoxide anion production, after induction of CXCR2 expression by PPAR-gamma ligands.


CONCLUSIONS
Our results provide a novel mechanism via which PPAR-gamma can enhance the immune response in human macrophages.
Rigamonti
Elena
E
Institut Pasteur de Lille, France.
Fontaine
Coralie
C
Lefebvre
Bruno
B
Duhem
Christian
C
Lefebvre
Philippe
P
Marx
Nikolaus
N
Staels
Bart
B
Chinetti-Gbaguidi
Giulia
G
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D054426:Chemokine CXCL2 / Q000494:pharmacology; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D016209:Interleukin-8; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D013481:Superoxides