Abstract
Control of apoptosis is fundamental for dendritic cell (DC) homeostasis. Numerous factors maintain DC viability throughout their lifespan, including inhibitor of apoptosis proteins. Among them, survivin is overexpressed in many human malignancies, but its physiological function in normal cells has not been fully delineated. Prostaglandin E2 (PGE2), also overproduced in several malignancies, has shown to induce proapoptotic and antiapoptotic effects in different cell types, including immune cells. In DC, PGE2 predominantly affects maturation and modulates immune functions. Here, we show that exposure of monocyte-derived DC to PGE2 (10(-5) M) for 72 h significantly increased DC survivin mRNA and protein expression. In contrast, DC, matured with lipopolysaccharide or tumor necrosis factor alpha, did not reveal survivin induction in response to PGE2. Following exposure to apoptotic stimuli, DC treated with PGE2 exhibited an overall increased viability compared with control DC, and this effect was correlated inversely with caspase-3 activation. Moreover, PGE2-treated, survivin-deficient DC demonstrated reduced viability in response to apoptotic stimuli. Further analysis indicated that PGE2 induced DC survivin expression in an E prostanoid (EP)2/EP4 receptor and phosphatidylinositol-3 kinase-dependent manner. These findings suggest that PGE2-dependent regulation of survivin is important in modulating apoptosis resistance in human DC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / radiation effects
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Caspase 3
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Caspases / metabolism
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Cell Differentiation / drug effects*
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Cell Differentiation / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Dendritic Cells / metabolism*
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Dinoprostone / metabolism
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Dinoprostone / pharmacology*
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Homeostasis / drug effects
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Homeostasis / physiology
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Humans
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Immunity, Cellular / drug effects
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Immunity, Cellular / physiology
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Inhibitor of Apoptosis Proteins
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Lipopolysaccharides / pharmacology
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Microtubule-Associated Proteins / metabolism*
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Monocytes / metabolism
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Neoplasm Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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RNA, Messenger / biosynthesis
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Receptors, Prostaglandin E / metabolism
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Survivin
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Lipopolysaccharides
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Microtubule-Associated Proteins
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Neoplasm Proteins
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PTGER2 protein, human
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PTGER4 protein, human
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RNA, Messenger
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Survivin
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Tumor Necrosis Factor-alpha
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Phosphatidylinositol 3-Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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Dinoprostone