Prostaglandin E2 promotes the survival of bone marrow-derived dendritic cells.
Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.
Vassiliou
Evros
E
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Sharma
Vikas
V
Jing
Huie
H
Sheibanie
Farzad
F
Ganea
Doina
D
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology / Q000502:physiology* / Q000637:transplantation; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000276:immunology; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D007052:Ibuprofen / Q000037:antagonists & inhibitors; D007425:Intracellular Membranes / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008297:Male; D008564:Membrane Potentials / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology; D051025:bcl-Associated Death Protein
C494820:Bad protein, mouse; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D006131:Growth Inhibitors; D008070:Lipopolysaccharides; D018078:Receptors, Prostaglandin E; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone; D007052:Ibuprofen