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* Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas;
Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain; and
Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Inflammatory mediators derived from arachidonic acid (AA) alter the function of dendritic cells (DC), but data regarding their biosynthesis resulting from stimulation of opsonic and nonopsonic receptors are scarce. To address this issue, the production of eicosanoids by human monocyte-derived DC stimulated via receptors involved in Ag recognition was assessed. Activation of Fc
R induced AA release, short-term, low-grade PG biosynthesis, and IL-10 production, whereas zymosan, which contains ligands of both the mannose receptor and the human β-glucan receptor dectin-1, induced a wider set of responses including cyclooxygenase 2 induction and biosynthesis of leukotriene C4 and IL-12p70. The cytosolic phospholipase A2 inhibitor pyrrolidine 1 completely inhibited AA release stimulated via all receptors, whereas the spleen tyrosine kinase (Syk) inhibitors piceatannol and R406 fully blocked AA release in response to immune complexes, but only partially blocked the effect of zymosan. Furthermore, anti-dectin-1 mAb partially inhibited the response to zymosan, and this inhibition was enhanced by mAb against DC-specific ICAM-3-grabbing nonintegrin (SIGN). Immunoprecipitation of DC lysates showed coimmunoprecipitation of DC-SIGN and dectin-1, which was confirmed using Myc-dectin-1 and DC-SIGN constructs in HEK293 cells. These data reveal a robust metabolism of AA in human DC stimulated through both opsonic and nonopsonic receptors. The FcR route depends on the ITAM/Syk/cytosolic phospholipase A2 axis, whereas the response to zymosan involves the interaction with the C-type lectin receptors dectin-1 and DC-SIGN. These findings help explain the distinct functional properties of DC matured by immune complexes vs those matured by β-glucans.
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1 This work was supported by grants from Plan Nacional de Salud y Farmacia (Grant SAF2004-01232), Fundación Ramón Areces, Junta de Castilla y León (Grant CSI05C05), and Red Temática de Investigación Cardiovascular. I.V. was the recipient of a grant from Banco de Santander-Central-Hispano. N.F. is under contract within the Ramón y Cajal Program (Ministerio de Educación y Ciencia of Spain and Fondo Social Europeo).
2 I.V. and N.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. M. Sánchez Crespo, Instituto de Biología y Genética Molecular, C/ Sanz y Forés s/n, 47003-Valladolid, Spain. E-mail address: mscres{at}ibgm.uva.es
4 Abbreviations used in this paper: DC, dendritic cell; AA, arachidonic acid; ALLN, N-acetyl-leucinyl-leucinyl-norleucinal; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; IC, immune complex; LT, leukotriene; MR, mannose receptor; PGN, peptidoglycan; PMN, polymorphonuclear leukocytes; HA, hemagglutinin.
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