Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions.
PGE(2) is a well-known immunomodulator produced in the immune response by APCs, such as dendritic cells (DCs), the most potent APC of the immune system. We investigated the PGE(2) biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE(2) and other proinflammatory mediators, such as leukotriene B(4) and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE(2) compared with the LPS-induced COX-2-produced PGE(2). Treatment of BM-DC with exogenous PGE(2) induced the production of large amounts of IL-10 and less IL-12p70. In addition, selective inhibition of COX-2, but not COX-1, was followed by significant decrements in PGE(2) and IL-10, a concomitant restoration of IL-12 production, and an enhancement of DC stimulatory potential. In contrast, we found no demonstrable role for leukotriene B(4) or NO. In view of the potential of PGE(2) to stimulate IL-10, we examined the possibility that the suppressive effect of PGE(2) is mediated via IL-10. We found that exogenous IL-10 inhibits IL-12p70 production in the presence of NS-398, a COX-2 selective inhibitor, while the inhibitory effects of PGE(2) were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE(2) up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.
Harizi
Hedi
H
Laboratoire d'Immunologie, Unité Mixte de Recherche Centre National de la Recherche Scientifique, Université Victor Segalen, Bordeaux 2, 33076 Bordeaux, France.
Juzan
Monique
M
Pitard
Vincent
V
Moreau
Jean-François
JF
Gualde
Norbert
N
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D015536:Down-Regulation; D015777:Eicosanoids / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D000906:Antibodies; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016753:Interleukin-10; D018664:Interleukin-12; D016718:Arachidonic Acid; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone