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J. Biol. Chem., Vol. 281, Issue 9, 5506-5514, March 3, 2006

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Regulation of Cytosolic Phospholipase A₂ Activation and Cyclooxygenase 2 Expression in Macrophages by the -Glucan Receptor^*

Saritha Suram, Gordon D. Brown¹, Moumita Ghosh, Siamon Gordon^¶, Robyn Loper, Philip R. Taylor^¶, Shizuo Akira^||, Satoshi Uematsu^||, David L. Williams^**, and Christina C. Leslie^¶2

From the Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa, ^¶Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom, Departments of Pathology and Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045 ^||Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan, ^**Department of Surgery, James H. Quillen College of Medicine, Johnson City, Tennessee 37614

Phagocytosis of non-opsonized microorganisms by macrophages initiates innate immune responses for host defense against infection. Cytosolic phospholipase A₂ is activated during phagocytosis, releasing arachidonic acid for production of eicosanoids, which initiate acute inflammation. Our objective was to identify pattern recognition receptors that stimulate arachidonic acid release and cyclooxygenase 2 (COX2) expression in macrophages by pathogenic yeast and yeast cell walls. Zymosan- and Candida albicans-stimulated arachidonic acid release from resident mouse peritoneal macrophages was blocked by soluble glucan phosphate. In RAW264.7 cells arachidonic acid release, COX2 expression, and prostaglandin production were enhanced by overexpressing the -glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)--D-glucan stimulated arachidonic acid release and COX2 expression, which were augmented in a Toll-like receptor 2 (TLR2)-dependent manner by macrophage-activating lipopeptide-2. However, arachidonic acid release and leukotriene C₄ production stimulated by zymosan and C. albicans were TLR2-independent, whereas COX2 expression and prostaglandin production were partially blunted in TLR2^–/– macrophages. Inhibition of Syk tyrosine kinase blocked arachidonic acid release and COX2 expression in response to zymosan, C. albicans, and particulate (1, 3)--D-glucan. The results suggest that cytosolic phospholipase A₂ activation triggered by the -glucan component of yeast is dependent on the immunoreceptor tyrosine-based activation motif-like domain of dectin-1 and activation of Syk kinase, whereas both TLR2 and Syk kinase regulate COX2 expression.

Received for publication, September 7, 2005 , and in revised form, December 8, 2005.

^* This work was supported by National Institutes of Health Grants HL34303 and HL61378 (to C. C. L.) and GM53522 and AI45829 (to D. L. W.) and by Wellcome Trust Grant 70579 (to P. T.). 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 A Wellcome Trust International Senior Research Fellow in Biomedical Science in South Africa.

² To whom correspondence should be addressed: Dept. of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1214; Fax: 303-270-2155; E-mail: lesliec{at}njc.org.

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