Regulation of cytosolic phospholipase A2 activation and cyclooxygenase 2 expression in macrophages by the beta-glucan receptor.
Phagocytosis of non-opsonized microorganisms by macrophages initiates innate immune responses for host defense against infection. Cytosolic phospholipase A(2) 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 beta-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)-beta-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 C(4) 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)-beta-D-glucan. The results suggest that cytosolic phospholipase A(2) activation triggered by the beta-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.
Suram
Saritha
S
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Brown
Gordon D
GD
Ghosh
Moumita
M
Gordon
Siamon
S
Loper
Robyn
R
Taylor
Philip R
PR
Akira
Shizuo
S
Uematsu
Satoshi
S
Williams
David L
DL
Leslie
Christina C
CC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002176:Candida albicans / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D015054:Zymosan / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099181:Dectin-1
D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D015777:Eicosanoids; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010741:Phospholipases A; D054467:Phospholipases A2; D011505:Protein-Tyrosine Kinases; D011971:Receptors, Immunologic; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D015054:Zymosan; D019061:src-Family Kinases; D000099181:Dectin-1; C493486:Tlr2 protein, mouse; C045268:beta-glucan receptor; C000606896:SYK protein, human; C000606897:Syk protein, mouse