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J. Biol. Chem., Vol. 282, Issue 46, 33405-33411, November 16, 2007

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Class A Scavenger Receptor-mediated Macrophage Adhesion Requires Coupling of Calcium-independent Phospholipase A₂ and 12/15-Lipoxygenase to Rac and Cdc42 Activation^*

Dejan M. Nikolic¹, Ming C. Gong, John Turk^¶2, and Steven R. Post³

From the Departments of Molecular and Biomedical Pharmacology and the Department of Physiology, University of Kentucky, Lexington, Kentucky 40536 and ^¶Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Class A scavenger receptors (SR-A) participate in multiple macrophage functions including adhesion to modified extracellular matrix proteins present in various inflammatory disorders such as atherosclerosis and diabetes. By mediating macrophage adhesion to modified proteins and increasing macrophage retention, SR-A may contribute to the inflammatory process. Eicosanoids produced after phospholipase A₂ (PLA₂)-catalyzed release of arachidonic acid (AA) are important regulators of macrophage function and inflammatory responses. The potential roles of AA release and metabolism in SR-A-mediated macrophage adhesion were determined using macrophages adherent to modified protein. SR-A-dependent macrophage adhesion was abolished by selectively inhibiting calcium-independent PLA₂ (iPLA₂) activity and absent in macrophages isolated from iPLA₂ ^–/– mice. Our results further demonstrate that 12/15-lipoxygenase (12/15-LOX)-derived, but not cyclooxygenase- or cytochrome P450-dependent epoxygenase-derived AA metabolites, are specifically required for SR-A-dependent adhesion. Because of their role in regulating actin polymerization and cell adhesion, Rac and Cdc42 activation were also examined and shown to be increased via an iPLA₂- and LOX-dependent pathway. Together, our results identify a novel role for iPLA₂-catalyzed AA release and its metabolism by 12/15-LOX in coupling SR-A-mediated macrophage adhesion to Rac and Cdc42 activation.

Received for publication, May 18, 2007 , and in revised form, September 13, 2007.

^* This work was supported in part by National Institutes of Health Grant HL075241 and an Established Investigator Award from the American Heart Association. 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.

¹ Recipient of a predoctoral fellowship from the American Heart Association (Ohio Valley Affiliate).

² Supported by United States Public Health Service Grants R37-DK34388, P41-RR00954, P60-DK20579, and P30-DK56341.

³ To whom correspondence should be addressed: Dept. of Molecular and BiomedicalPharmacology, UKMedicalCenter-MS305, Lexington, KY40536-0298. Tel.: 859-323-4933; Fax: 859-257-3646; E-mail: spost{at}uky.edu.

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