Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF-α production by enhancing serotonin release from enterochromaffin cells.

Antagonists of the 5-hydroxytryptamine (serotonin) 3 receptor (5-HT3R) have anti-inflammatory and anti-apoptotic activities, but the detailed, underlying mechanisms are not well understood. We focused on anti-apoptotic activities via 5-HT3R signaling to clarify the underlying mechanisms. Mice were administered 5-fluorouracil (5-FU), which induced apoptosis in intestinal epithelial cells. Coadministration with 5-HT3R antagonists or agonists tended to decrease or increase the number of apoptotic cells, respectively. In serotonin 3A receptor (5-HT3AR) null (HTR3A(-/-)) mice, the number of apoptotic cells induced by 5-FU was decreased compared with that in wild-type (WT) mice. Bone marrow (BM) transplantation was performed to determine if BM-derived immune cells regulated 5-FU-induced apoptosis, but they were found to be unrelated to this process. Data from 5-HT3AR/enhanced green fluorescent protein reporter mice revealed that 50% of enterochromaffin (EC) cells expressed 5-HT3AR, but the number of apoptotic cells induced by 5-FU in the intestinal crypt organoids of HTR3A(-/-) mice was not altered compared with WT mice. In contrast, plasma 5-HT concentrations in WT mice but not in HTR3A(-/-) mice administered 5-FU were increased significantly. In conclusion, 5-HT3R signaling may enhance 5-HT release, possibly from EC cells intravascularly, or paracrine, resulting in increases in plasma 5-HT concentration, which in turn, enhances apoptotic activities induced by 5-FU.Mikawa, S., Kondo, M., Kaji, N., Mihara, T., Yoshitake, R., Nakagawa, T., Takamoto, M., Nishimura, R., Shimada, S., Ozaki, H., Hori, M. Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF- production by enhancing serotonin release from enterochromaffin cells.