Engagement of the high-affinity IgE receptor (Fc epsilon RI) can be either protective or non-protective against apoptotic cell death (ACD) in bone marrow-derived murine mast cells (BMMCs) after IL-3 withdrawal, depending on the avidity between IgE and its antigen. We recently reported that protein L (PpL), a bacterial Ig kappa-binding soluble protein, is able to stimulate intracellular signaling to induce activation of BMMCs by interacting with the IgE kappa-Fc epsilon RI complex. However, it is unclear if cross-linking of Fc epsilon RI with lgE kappa and PpL prevents or enhances IL-3-dependent ACD in BMMCs. In the present study, we found that IL-3-dependent ACD of BMMCs is accelerated by loading soluble PpL in the presence of IgE kappa-occupied Fc epsilon RI alpha. For this purpose, soluble PpL was incorporated into the BMMCs. Unlilce soluble PpL, immobilized PpL failed to enhance ACD, although both forms of PpL induced IL-6 production equally in BMMCs. In addition, we observed that DNS5-BSA protected anti-DNS IgE-sensitized BMMCs from IL-3 depletion-mediated ACD by inducing the production of autocrine IL-3. In contrast, DNS5-PpL enhanced IL-3 withdrawal-induced ACD of anti-DNS IgE-sensitized BMMCs and reduced the production of autocrine IL-3. These findings suggest that PpL increases IL-3 withdrawal-induced ACD of IgE kappa-sensitized BMMCs by incorporating PpL into the BMMCs and that this internalized PpL may interfere with survival signals via Fc epsilon RI. (C) 2014 Elsevier Inc. All rights reserved.