PGE(2) Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

Increased mast cell numbers are observed at sites of allergic inflammation and restoration of normal mast cell numbers is critical to the resolution of these responses. Early studies showed that cytokines protect mast cells from apoptosis, suggesting a simple model in which diminished cytokine levels during resolution leads to cell death. The report that prostaglandins can contribute both to recruitment and to the resolution of inflammation together with the demonstration that mast cells express all four PGE(2) receptors raises the question of whether a single PGE(2) receptor mediates the ability of PGE(2) to regulate mast cell survival and apoptosis. We report here that PGE(2) through the EP3 receptor promotes cell death of mast cells initiated by cytokine withdrawal. Furthermore, the ability of PGE(2) to limit reconstitution of tissues with cultured mast cells is lost in cell lacking the EP3 receptor. Apoptosis is accompanied by higher dissipation of mitochondrial potential (ΔΨ(m)), increased caspase-3 activation, chromatin condensation, and low molecular weight DNA cleavage. PGE(2) augmented cell death is dependent on an increase in intracellular calcium release, calmodulin dependent kinase II and MAPK activation. Synergy between the EP3 pathway and the intrinsic mitochondrial apoptotic pathway results in increased Bim expression and higher sensitivity of mast cells to cytokine deprivation. This supports a model in which PGE(2) can contribute to the resolution of inflammation in part by augmenting the removal of inflammatory cells in this case, mast cells.