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

Abstract

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