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A more recent version of this article appeared on March 3, 2006
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Papers In Press, published online ahead of print January 3, 2006
J. Biol. Chem, 10.1074/jbc.M509824200
Submitted on September 7, 2005
Revised on December 8, 2005
Accepted on January 3, 2006

Regulation of cytosolic phospholipase A2 activation and cyclooxygenase 2 expression in macrophages by the beta -glucan receptor

Saritha Suram, Gordon D. Brown, Moumita Ghosh, Siamon Gordon, Robyn Loper, Philip R. Taylor, Shizuo Akira, Satoshi Uematsu, David L. Williams, and Christina C. Leslie

Pediatrics Dept., National Jewish Medical and Research Center, Denver, CO 80206

Corresponding Author: lesliec{at}njc.org

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 over-expressing the ß-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1,3)-ß-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 Candida 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, Candida albicans and particulate (1,3)-ß-D-glucan. The results suggest that cytosolic phospholipase A2 activation triggered by the ß-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.


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