Prostaglandin E2 synthesis in human monocyte-derived dendritic cells

Norgauer, Johannes; Ibig, Yvonne; Gmeiner, Doris; Herouy, Yared; Fiebich, Bernd L.

doi:10.3892/ijmm.12.1.83

Cited by 11 publications

(8 citation statements)

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“…This is in agreement with previous reports that p38 and JNK kinases are involved in DC migration 28 , 36 , 37 . p38 activity triggers synthesis and secretion of PGE2 38 and this might explain the observed enhancement in PGE2 production induced by CyaA‐AC − in BMDC. Interestingly, K + efflux from cells permeabilized by pore‐forming toxins was recently shown to trigger specifically the phosphorylation of p38 (ref.…”

Section: Discussionsupporting

confidence: 93%

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

et al. 2015

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The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.

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Section: Discussionsupporting

confidence: 93%

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

et al. 2015

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“…EP2 and EP4 receptors are efficient for mediating PGE 2 -induced modulation of activated DC functions, because the expression of EP2 and EP4 receptors are enhanced by LPS in a dose-dependent manner (Harizi et al 2003). LPS-induced PGE 2 synthesis by DCs depends on the activated p38 MAPK-induced COX-2 expression, because p38 MAPK inhibitors block the LPS-induced COX-2 expression and PGE 2 release (Norgauer et al 2003). PGE 2 inhibits TNF-a release from LPS stimulated murine bone marrow (BM)-derived DCs (BM-DCs) .…”

Section: Effects Of Psls On Dcsmentioning

confidence: 99%

Phosphatidylserine-Containing Liposomes: Potential Pharmacological Interventions Against Inflammatory and Immune Diseases Through the Production of Prostaglandin E2 After Uptake by Myeloid Derived Phagocytes

Nakanishi

2011

Arch. Immunol. Ther. Exp.

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Phosphatidylserine (PS), which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet at the early stage of apoptosis. The PS externalization provides a signal for phagocytes to initiate uptake of apoptotic cells. After phagocytosis of apoptotic cells, phagocytes induce the secretion of anti-inflammatory mediators including prostaglandin E(2) (PGE(2)). PS-containing liposomes (PSLs) can mimic the effects of apoptotic cells on phagocytes to induce the secretion of PGE(2). PSLs induce the PGE(2) secretion from microglia without induction of either cyclooxygenase (COX)-2 or microsomal prostaglandin E synthase (mPGES)-1. PSLs are found to rather utilize COX-1/mPGES-2 system to produce PGE(2) secretion and then shift microglia and macrophages from pro- to anti-inflammatory phenotype by an autocrine action of PGE(2). Moreover, PSLs inhibit the maturation of dendritic cells and osteoclast precursors. Therefore, PSLs will be potential pharmacological interventions for inflammatory and immune diseases through feedback mechanism utilizing PGE(2).

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“…Interestingly, CT has been shown to increase the production of PGE 2 in many cell types, including DC, through the release of arachidonic acid (7,8,11,18,39). Nitric oxide (NO) and superoxide anions have also recently gained attention for their ability to directly activate DC or to synergize with other agonists that activate DC (29,41).…”

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confidence: 99%

Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E₂and Nitric Oxide

Bagley

Abdelwahab

Tuskan

et al. 2006

Clin Vaccine Immunol

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Cholera toxin (CT) is a potent adjuvant that activates dendritic cells (DC) by increasing intracellular cyclic AMP (cAMP) levels. In vivo and in vitro, very small amounts of CT induce potent adjuvant effects and activate DC. We hypothesized that DC intoxicated by CT may release factors that enhance their own maturation and induce the maturation of toxin-free bystander DC. Through the use of mixed cultures and transwell cultures, we found that human monocyte-derived DC (MDDC) pulsed with CT or other cAMP-elevating agonists induce the maturation of bystander DC. Many DC agonists including CT increase the production of prostaglandin E 2 (PGE 2 ) and nitric oxide (NO). For this reason, we determined whether the actions of PGE 2 or NO are involved in the maturation of MDDC induced by CT or dibutyryl-cAMP (d-cAMP). We found that blocking the production of PGE 2 or blocking prostaglandin receptors inhibited MDDC maturation induced by CT and d-cAMP. Likewise, sequestering NO or blocking the downstream actions of NO resulted in the inhibition of MDDC maturation induced by CT and d-cAMP. These results indicate that endogenously produced factors including PGE 2 and NO contribute to the maturation of DC induced by CT and that these factors participate in bystander DC maturation. The results of this study may help explain why bacterial toxins that elevate cAMP are such potent adjuvants.Understanding the intercellular and intracellular signaling processes that lead to dendritic cell (DC) maturation is important for determining how these cells initiate immune responses to foreign antigens. Monocyte-derived DC (MDDC), produced by culturing monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 6 to 7 days, are phenotypically equivalent to the immature DC that reside in peripheral tissues (45). However, it is becoming increasingly evident that the kinetics of in vivo DC differentiation from monocytes may not be reflected by the long-term in vitro culture conditions required to generate MDDC. A recent study showed that mature DC can be generated from human monocytes in as little as 48 h (14). We have studied the transition of monocytes to DC in vitro and have also generated a shortened protocol for the in vitro generation of DC. With our protocol, MDDC are matured after only 4 days of culture in the presence of GM-CSF and IL-4 (2-4). In our hands, MDDC at day 4 are more responsive to activation than MDDC at days 5 to 7.Cholera toxin (CT) is an AB5 enterotoxin produced by Vibrio cholerae, the primary causative agent of the disease cholera. CT consists of a 27-kDa catalytic A domain anchored in a ring of five identical 11.7-kDa B subunits (40). The B pentamer of CT binds to GM1 gangliosides on cell membranes (28). CT has a Lys/Arg-Asp-Glu-Leu ([K/R]DEL) signal sequence at the C terminus of its A domain. This sequence is believed to target the toxin to the endoplasmic reticulum, where the A1 subunit (disguised as a misfolded host protein) is transported to the cytoplasm by the endoplasm...

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Prostaglandin E2 synthesis in human monocyte-derived dendritic cells

Cited by 11 publications

References 0 publications

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

Phosphatidylserine-Containing Liposomes: Potential Pharmacological Interventions Against Inflammatory and Immune Diseases Through the Production of Prostaglandin E2 After Uptake by Myeloid Derived Phagocytes

Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E₂and Nitric Oxide

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Prostaglandin E2 synthesis in human monocyte-derived dendritic cells

Cited by 11 publications

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Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells

Phosphatidylserine-Containing Liposomes: Potential Pharmacological Interventions Against Inflammatory and Immune Diseases Through the Production of Prostaglandin E2 After Uptake by Myeloid Derived Phagocytes

Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E2and Nitric Oxide

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Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8⁺ and CD4⁺ T cells

Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E₂and Nitric Oxide