Activation of p38 mitogen-activated protein kinase is required for tumor necrosis factor-α-supported proliferation of leukemia and lymphoma cell lines

To elucidate mechanisms of tumor necrosis factor alpha (TNF-alpha)-induced proliferation of a number of human leukemia and lymphoma cell lines, we examined the role of p38 mitogen-activated protein kinase (MAPK) in TNF-alpha signaling in Mo7e and Hut-78 cells. TNF-alpha-dependent p38 MAPK activation was detected in both Mo7e and Hut-78 cells and was blocked by the p38 MAPK inhibitor, SB203580. Ablation of p38 MAPK activity by SB203580 abrogated TNF-alpha-induced Mo7e cell proliferation and TNF-alpha-dependent autocrine growth of Hut-78. As we have shown previously that activation of the nuclear factor kappa B (NF-kappa B) is also required for TNF-alpha-induced Mo7e cell proliferation, the involvement of p38 MAPK in NF-kappa B activation was assessed. SB203580 did not affect TNF-alpha-signaled nuclear translocation and DNA-binding activity of NF-kappa B, and inhibition of NF-kappa B function did not affect TNF-alpha-induced p38 MAPK activation, indicating that these events are not dependent on each other. However, SB203580 depressed the expression of TNF-kappa B-dependent genes, as monitored by a kappa B-driven reporter gene. Our findings demonstrate that activation of both p38 MAPK and NF-kappa B plays a critical role in TNF-alpha-mediated survival and proliferation of human leukemia and lymphoma cells, and p38 MAPK acts at least in part by facilitating the transcriptional activation function of NF-kappa B.