title: Prostaglandins inhibit 5-lipoxygenase-activating protein expression and leukotriene B4 production from dendritic cells via an IL-10-dependent mechanism.
abstract: PGs produced from arachidonic acid by the action of cyclooxygenase enzymes play a pivotal role in the regulation of both inflammatory and immune responses. Because leukotriene B4 (LTB4), a product of 5-lipoxygenase (5-LO) pathway, can exert numerous immunoregulatory and proinflammatory activities, we examined the effects of PGs on LTB4 release from dendritic cells (DC) and from peritoneal macrophages. In concentration-dependent manner, PGE1 and PGE2 inhibited the production of LTB4 from DC, but not from peritoneal macrophage, with an IC50 of 0.04 microM. The same effect was observed with MK-886, a 5-LO-activating protein (FLAP)-specific inhibitor. The decreased release of LTB4 was associated with an enhanced level of IL-10. Furthermore, the inhibition of LTB4 synthesis by PGs was significantly reversed by anti-IL-10, suggesting the involvement of an IL-10-dependent mechanism. Hence, we examined the effects of exogenous IL-10 on the 5-LO pathway. We demonstrate that IL-10 suppresses the production of LTB4 from DC by inhibiting FLAP protein expression without any effect on 5-LO and cytosolic phospholipase A2. Taken together, our results suggest links between DC cyclooxygenase and 5-LO pathways during the inflammatory response, and FLAP is a key target for the PG-induced IL-10-suppressive effects.
authors.affiliation: Laboratoire d'Immunologie, Center National de la Recherche Scientifique, Unité Mixte de Recherche 5540, Université de Bordeaux 2, Bordeaux, France.
authors.forename: Hedi
authors.initials: H
authors.lastname: Harizi
authors.forename: Monique
authors.initials: M
authors.lastname: Juzan
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.forename: Norbert
authors.initials: N
authors.lastname: Gualde
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D015777:Eicosanoids / Q000096:biosynthesis; D054513:Group IV Phospholipases A2; D007106:Immune Sera / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009685:Nuclear Envelope / Q000187:drug effects / Q000201:enzymology; D010741:Phospholipases A / Q000096:biosynthesis / Q000378:metabolism; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D000276:Adjuvants, Immunologic; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D007106:Immune Sera; D008565:Membrane Proteins; D011453:Prostaglandins; D016753:Interleukin-10; D007975:Leukotriene B4; D000001:Calcimycin; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; D015232:Dinoprostone