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J. Biol. Chem., Vol. 279, Issue 9, 8300-8315, February 27, 2004

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Peroxisome Proliferator-activated Receptor Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism^*

Alan P. Kumar, F. Javier Piedrafita, and Wanda F. Reynolds

From the Sidney Kimmel Cancer Center, San Diego, California 92121

A functional myeloperoxidase (MPO) promoter polymorphism, -463GA, has been associated with incidence or severity of inflammatory diseases, including atherosclerosis and Alzheimer's disease, and some cancers. The polymorphism is within an Alu element encoding four hexamer repeats recognized by nuclear receptors (AluRRE). Here we show that peroxisome proliferator-activated receptor (PPAR) agonists strongly regulate MPO gene expression through the AluRRE. Opposite effects were observed in granulocyte/macrophage colony-stimulating factor (GMCSF)- versus macrophage colony-stimulating factor (MCSF)-derived macrophages (M): Expression was markedly up-regulated (mean 26-fold) in MCSF-M and down-regulated (34-fold) in GMCSF-M. This was observed with rosiglitazone and three other PPAR ligands of the thiazolidinedione class, as well as the natural prostaglandin metabolite 15-deoxy-^12,14 prostaglandin J₂. The selective PPAR antagonist, GW9662, blocked both the positive and negative effects on MPO expression. Gel retardation assays showed PPAR bound hexamers 3/4, and estrogen receptor- bound hexamers 1/2, with -463A in hexamer 1 enhancing binding. Estrogen blocked PPAR effects on MPO expression, especially for the A allele. Charcoal filtration of fetal calf serum eliminated the block of PPAR, whereas replenishing the medium with 17-estradiol reinstated the block. These findings suggest a model in which estrogen receptor binds the AluRRE, preventing PPAR binding to the adjacent site. The positive and negative regulation by PPAR ligands, and the block by estrogen, was also observed in transgenic mice expressing the G and A alleles. The mouse MPO gene, which lacks the primate-specific AluRRE, was unresponsive to PPAR ligands, suggesting the human MPO transgenes will enhance the utility of mouse models for diseases involving MPO, such as atherosclerosis and Alzheimer's.

Received for publication, October 23, 2003 , and in revised form, December 3, 2003.

^* This work was supported by National Institutes of Health Grant RO1 AG17879 (to W. F. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121. Tel.: 858-410-4197; Fax: 858-450-3251; E-mail: wreynolds{at}skcc.org.

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