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This version published online on March 6, 2008
Molecular Endocrinology, doi:10.1210/me.2007-0525
A more recent version of this article appeared on June 1, 2008
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Submitted on November 23, 2007
Accepted on February 26, 2008

Arginase I Induction by Modified Lipoproteins in Macrophages: A PPAR{gamma}/{delta}-Mediated Effect That Links Lipid Metabolism and Immunity

Alejandro Gallardo-Soler, Carlos Gómez-Nieto, María Luisa Campo, Chaitra Marathe, Peter Tontonoz, Antonio Castrillo, and Inés Corraliza*

Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Veterinaria, Universidad de Extremadura, 10071, Cáceres, Spain (A.G.-S., M.L.C., I.C.); Unidad de Parasitología, Facultad de Veterinaria, Universidad de Extremadura, 10071, Cáceres, Spain (C.G.-N.); Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095 (P.T., C.M.); Departamento de Bioquímica y Biología Molecular, Universidad de Las Palmas de Gran Canaria, Las Palmas 35016, Spain (A.C.)

* To whom correspondence should be addressed. E-mail: corragen{at}unex.es.

Macrophages are phagocytic cells that play essential roles in innate immunity and lipid homeostasis. The uptake of modified lipoproteins is an important early event in the development of atherosclerosis. We analyzed the ability of modified LDL (oxidized and acetylated) to alter the expression and activity of arginases (ArgI and ArgII) in macrophages. We show that ArgI expression is potently induced by both oxLDL and acLDL in macrophages. We further show that this effect is mediated by peroxisome proliferator-activated receptors (PPARs). Arginase I expression is highly responsive to agonists for PPAR{gamma} and PPAR{delta} but not PPAR{alpha}. Moreover, the induction of ArgI by both PPAR agonists and IL-4 is blocked in macrophages from PPAR{gamma}- and {delta}-deficient mice. Functionally, PPAR activity induces macrophage activation towards a more Th2 immune phenotype in a model of Leishmania major infection. We show that PPAR{gamma} and {delta} ligands promote intracellular amastigote growth in infected macrophages, and this effect is dependent on both PPAR expression and arginase activity. Collectively, our results strongly suggest that arginase I is a key marker of the alternative program triggered by PPARs in macrophages.
Key words: Arginase I • macrophages • oxLDLs • PPARs

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ
Ligands:   GW 1929  |  GW 9662  |  GW 7647  |  GW0742X  |  Pirinixic acid  |  9-cis-Retinoic acid  |  15-Deoxy-Δ12  |  Rosiglitazone





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