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J. Biol. Chem., Vol. 283, Issue 31, 21640-21648, August 1, 2008

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Macrophage Secretory Phospholipase A₂ Group X Enhances Anti-inflammatory Responses, Promotes Lipid Accumulation, and Contributes to Aberrant Lung Pathology^*

Daniëlle M. J. Curfs¹, Stijn A. I. Ghesquiere, Monique N. Vergouwe, Ingeborg van der Made, Marion J. J. Gijbels, David R. Greaves^¶, J. Sjef Verbeek^||, Marten H. Hofker^**, and Menno P. J. de Winther²

From the Departments of Molecular Genetics, and Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands, the ^¶Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom, the ^||Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands, and the ^**Laboratory of Pathology and Laboratory Medicine, University Medical Center Groningen, Antonie van Deusinglaan 1, 9713 AV Groningen, The Netherlands

Secreted phospholipase A2 group X (sPLA₂-X) is one of the most potent enzymes of the phospholipase A₂ lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and low-density lipoproteins (LDL), has implicated sPLA₂-X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA₂-X enzyme activity in vitro and in vivo, by generating sPLA₂-X-overexpressing macrophages and transgenic macrophage-specific sPLA₂-X mice. Our results show that sPLA₂-X expression inhibits macrophage activation and inflammatory responses upon stimulation, characterized by reduced cell adhesion and nitric oxide production, a decrease in tumor necrosis factor (TNF), and an increase in interleukin (IL)-10. These effects were mediated by an increase in IL-6, and enhanced production of prostaglandin E₂ (PGE₂) and 15-deoxy-12,14-prostaglandin J₂ (PGJ₂). Moreover, we found that overexpression of active sPLA₂-X in macrophages strongly increases foam cell formation upon incubation with native LDL but also oxidized LDL (oxLDL), which is mediated by enhanced expression of scavenger receptor CD36. Transgenic sPLA₂-X mice died neonatally because of severe lung pathology characterized by interstitial pneumonia with massive granulocyte and surfactant-laden macrophage infiltration. We conclude that overexpression of the active sPLA₂-X enzyme results in enhanced foam cell formation but reduced activation and inflammatory responses in macrophages in vitro. Interestingly, enhanced sPLA₂-X activity in macrophages in vivo leads to fatal pulmonary defects, suggesting a crucial role for sPLA₂-X in inflammatory lung disease.

Received for publication, December 31, 2007 , and in revised form, May 15, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

² An established investigator of the Netherlands Heart Foundation (2007T067), and is supported by the Netherlands Organization for Scientific Research (NWO), Grants 906-02-075, Vidi nr 917-66-329, and by the European Vascular Genomics Network (EVGN).

¹ To whom correspondence should be addressed: Dept. of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University. Universiteitssingel 50, 6229 ER Maastricht, The Netherlands. Tel.: 31-43-388-1746; Fax: 31-43-4574; E-mail: d.curfs{at}gen.unimaas.nl.

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