Exogenous but not endogenous prostanoids regulate cytokine secretion from murine bone marrow dendritic cells: EP2, DP, and IP but not EP1, EP3, and FP prostanoid receptors are involved.
Murine bone marrow-derived dendritic cells (DC), stimulated with lipopolysaccharide (LPS) and/or LPS+interferon-gamma (IFN-gamma), secrete a variety of inflammatory mediators which may modulate their functions. We have examined the potential for exogenous prostanoids, acting in a paracrine fashion, and endogenous prostanoids, acting in an autocrine fashion, to regulate secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10, and IL-12 in DC. In order to identify receptors mediating these effects, DC were treated in vitro with receptor-selective prostanoids. Agonists of cyclic AMP-elevating receptors, namely, prostaglandin E(2) (PGE(2)), butaprost (EP(2) receptor), iloprost (IP receptor), and BW245C (DP receptor), dose-dependently inhibited the release of IL-6, TNF-alpha, and IL-12 and enhanced the release of IL-10 from LPS-stimulated DC, with TNF-alpha secretion being the most strongly affected. In contrast, 15-deoxy-Delta(12,14)-PGJ(2)-an activator of nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) receptors-inhibited release of all tested cytokines. Exogenous prostanoids, cyclic AMP-elevating analogs, lost their ability to modulate cytokine release in cells pre-incubated for 4 h with LPS, indicating that prostanoids may affect DC functions during initial phases of LPS stimulation only. Sulprostone and (+)-fluprostenol failed to modulate any of responses tested, suggesting lack of involvement/expression of EP(1), EP(3), and FP receptors in DC activation. In order to examine the role of endogenous prostanoids, DC were treated with inhibitors of cyclooxygenases (COX). At concentrations that completely blocked PGE(2) release, neither indomethacin (nonselective inhibitor) nor rofecoxib (COX-2-selective inhibitor) influenced cytokine release from LPS-stimulated DC. Thus, cytokine release from LPS-stimulated DC does not seem to be autoregulated by endogenous prostanoids, whereas in vivo regulatory function may be fulfilled in a paracrine manner by PGD(2), PGE(2), and PGI(2) released from neighboring cells.
Józefowski
Szczepan
S
Department of Immunology, Jagiellonian University Medical College, 18 Czysta Street, 31-121, Cracow, Poland.
Bobek
Małgorzata
M
Marcinkiewicz
Janusz
J
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011453:Prostaglandins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D044006:Receptors, Epoprostenol / Q000187:drug effects; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000187:drug effects; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007202:Indicators and Reagents; D015850:Interleukin-6; D007527:Isoenzymes; D011453:Prostaglandins; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; D012333:RNA, Messenger; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014409:Tumor Necrosis Factor-alpha; C034671:prostaglandin F2alpha receptor; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C036293:prostaglandin D2 receptor