P161	Peroxisome Proliferator-activated Receptor (PPAR) gamma upregulates CXCR2 expression in human macrophages and atherosclerotic plaques.
1C.Fontaine, 2E.Rigamonti, 2Chr.Duhem, 2J.Bertout, 1J-C.Fruchart, 3N.Marx, 1G.Chinetti-Gbaguidi, 1B.Staels
1Institut Pasteur de Lille INSERM U545, Lille, FR; 2Lille, FR; 3Ulm, DE & 2Lille, FR.

IL-8 and related Glu-Leu-Arg (ELR+) CXC chemokines have been suggested to be involved in the pathogenesis of atherosclerosis. These chemokines and their receptor CXCR2 are known to play a role in the recruitment and activation of mononuclear phagocytes in pathological conditions in which IL-4 is expressed, such as Th2 immune response. The nuclear receptor PPARgamma, which is implicated in macrophage inflammatory responses to lipids, has also been linked to IL-4 activity, through enhanced levels of 12,15 lipooxygenase, an enzyme that is involved in arachidonate metabolism. In the present study, the modulating effect of PPARgamma on the expression of CXCR2 and its functional consequences were investigated in macrophages. In primary human macrophages, PPARgamma activation increased CXCR2 membrane protein expression as measured by flow cytometry and western blot analysis. This regulation occurred at the gene expression level since CXCR2 mRNA was increased by synthetic PPARgamma ligands rosiglitazone and Gw1929. Transient transfection assays and gel shift analysis indicated that PPARgamma activation induced CXCR2 promoter activity by binding to a PPRE (PPAR Response Element). Human macrophages did not respond to CXCR2 ligands (IL-8/GroBeta) in terms of superoxide anion production but this response could be readily induced following exposure to PPARgamma ligands and subsequent up-regulation of CXCR2. Moreover, CXCR2 mRNA was expressed in human atherosclerotic plaques and induced after rosiglitazone treatment. In conclusion, our results identify a new link between PPARgamma and IL-4 pathway via CXCR2 up-regulation in human macrophages. PPARgamma may thus contribute to the accumulation and positioning of IL-4-alternatively activated macrophages in Th-2 dominated responses.

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