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‐HT 3 R) have anti‐inflammatory and anti‐apoptotic activities, but the detailed, underlying mechanisms are not well understood. We focused on anti‐apoptotic activities via 5‐HT 3 R signaling to clarify the underlying mechanisms. Mice were administered 5‐fluorouracil (5‐FU), which induced apoptosis in intestinal epithelial cells. Coadministration with 5‐HT 3 R antagonists or agonists tended to decrease or increase the number of apoptotic cells, respectively. In serotonin 3A receptor (5‐HT 3A R) 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‐HT 3A R/enhanced green fluorescent protein reporter mice revealed that 50% of enterochromaffin (EC) cells expressed 5‐HT 3A R, 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‐HT 3 R 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‐α production by enhancing serotonin release from enterochromaffin cells. FASEB J. 33, 1669–1680 (2019). www.fasebj.org