Prostaglandin E_2 Promotes the Survival of Bone Marrow-Derived Dendritic Cells

摘要

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 mitochondria! 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.