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Cysteinyl-Leukotriene Receptor Type 1 Expression and Function Is Down-Regulated during Monocyte-Derived Dendritic Cell Maturation with Zymosan: Involvement of IL-10 and Prostaglandins¹

Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada

TLRs sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). DCs have been shown to produce leukotrienes and, conversely, leukotrienes are known to modulate several DC functions. In this study, we examined the modulation of expression and function of cysteinyl-leukotriene receptor type 1 (CysLT1) on human monocyte-derived DCs during their differentiation and subsequent maturation with zymosan, a TLR2 agonist. Maturation of DCs with zymosan reduced CysLT1 mRNA levels and protein expression in a time-dependent fashion and was associated with a diminution of functional responsiveness to leukotriene D₄ as assessed by intracellular calcium mobilization, CCL2 and CCL3 production, and chemotaxis. The effect of zymosan was mediated by both TLR2 and dectin-1 activation. Zymosan also induced a rapid expression of cyclooxygenase-2 and the production of PGE₂ and IL-10. Addition of an anti-IL-10 neutralizing Ab or inhibitors of cyclooxygenase greatly reduced the ability of zymosan to down-regulate CysLT1 expression. Down-regulation of CysLT1 expression by zymosan could be reproduced by a combination of IL-10 and PGE₂, and was dependent on MAPK activation. Taken together, our findings indicate that zymosan down-regulates CysLT1 expression in DCs with consequently reduced functional responsiveness of the cells to leukotriene D₄ stimulation. This effect is partially dependent on an endogenous production of PGs and IL-10 by DCs.

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 This work was supported by a grant from the Canadian Institutes of Health Research (to J.S. and M.R.-P.). J.S. and M.R.-P. are members of the Fonds de la Recherche en Santé du Québec-funded Centre de Recherche Clinique Étienne Lebel. M.R.-P. is the holder of a Canada Research Chair in Inflammation.

² Address correspondence and reprint requests to Dr. Marek Rola-Pleszczynski, Division of Immunology and Allergy, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke, Quebec J1H 5N4, Canada. E-mail address: Marek.Rola-Pleszczynski{at}USherbrooke.ca

³ Abbreviations used in this paper: DC, dendritic cell; MoDC, monocyte-derived DC; iDC, immature DC; mDC, mature DC; LT, leukotriene; cysLT, cysteinyl-LT; CysLT1, cysLT receptor type 1; poly(I:C), polyinosinic-polycytidylic acid; COX, cyclooxygenase; PAF, platelet-activating factor; TIR, Toll/IL-1R; TRIF, TIR domain–containing adaptor-inducing IFN-β.