24. TPA-induced Apoptosis Is Mediated by TNF in Human Monocytic U937 Cells

Makoto Akashi, Misao Haehiya, Sakae Tanosaki, Yoshikazu Kuroiwa, Yoshiko Kawase and Toshiyasu Ilirama

Keywords: apoptosis, TPA,TNFa, TNFRI, MAPK

12-0-tetradecanoylphorbol-13-acetate (TPA), a phorbol ester which is known as a tumor promoter induces differentiation of myeloid cells and suppresses their proliferation. We studied the regulation of apoptosis by TPA in human monocytic cell line U937 cells that lack p53. Untreated U937 cells constitutively underwent apoptosis and TPA en hanced apoptosis in these cells. Further studies showed that TPA increased production of tumor necrosis factor-(TNF) in U937 cells, and exogenously -added TNF a induced apoptosis. Moreover, the induction of apoptosis by TPA was blocked by anti TNFa antibody. Similar results were obtained in the myeloblastic cell line KY821 cells. We also found that the induction of apoptosis by TPA was increased in cells overexpressed with TNF receptor 1 (TNFR1) but not in control cells. Furthermore, TPA failed to induce the production of TNF and apoptosis in cells with either their protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) pathway blocked. Our results indicate that TPA induces apoptosis, at least in part, through a pathway which requires endogenous production of TNF in U937 cells. Our data also suggest that the induction of apoptosis by TPA occurs through activation of PKC and MAPK, and TNF us an autocrine-stimulating factor for the induction of apoptosis in these cells.

Publication:
Takada, Y., Ilachiya, IVI., 0 sawa, Y., Flasegawa, Y., Ando, K., Kobayashi, Y. and Akashi, M : J. Biol. chem. 274 28286-28292 1999.