Notch signaling regulates cell density-dependent apoptosis of NIH 3T3 through an IL-6/STAT3 dependent mechanism

Apoptosis is a physiological process that plays a critical maintenance role in cellular homeostasis. Previous reports have demonstrated that cells undergo apoptosis in a cell density-dependent manner, which is regulated, in part, by signal transducers and activators of transcription (STAT) 3. The molecular mechanisms regulating cell density-dependent apoptosis, however, has not been thoroughly investigated to date. Since Notch signaling is activated via direct cell-to-cell contact and plays a pivotal role in cell fate decisions, we examined the role of Notch signaling in cell density-dependent apoptosis of mouse embryonic fibroblasts NIH 3T3 cells. With the increase in cell density, IL-6 expression was induced, which was necessary for STAT3 activation as well as apoptosis regulation. Notch signaling was also activated in a cell-density dependent manner. Blocking Notch signaling either through siRNA-mediated targeting of Jagged1 expression or gamma-secretase inhibitor treatment demonstrated that Notch signaling activation was necessary for IL-6 induction. Constitutive activation of Notch signaling via the overexpression of Notch1 intracellular domain was sufficient for the induction of IL-6, which was mediated via direct transcriptional activation. Taken together, our study indicates that Notch signaling regulates cell density-dependent apoptosis through IL-6/STAT3-dependent mechanism. Consequently, Notch signaling might represent a novel therapeutic target in diseases characterized by dysregulated apoptosis.