Radiation-induced apoptosis through endogenous TNFa production is mediated by MEK, p38MAPK, PI3K or JNK in Jurkat T leukemia cells

Tumor necrosis factor alpha (TNFa) is a unique pro-inflammatory cytokine whose signaling pathways are linked to both pro- and anti- apoptotic responses in many types of cells, and is produced upon radiation exposure. Previously we have shown that radiation induces apoptosis through the caspase pathway requiring TNFa production in human Jurkat T leukemia cells lacking functional p53. The TNFa expression is regulated by a transcription factor, early growth response-1 (Egr-1) in cell lines lacking p53. To better understand the mechanism of TNFa expression after high dose radiation, we used inhibitors of the MEK (PD98059), p38MAPK (SB203580), PI3K (LY294002) and JNK (SP600125) pathways and examined Egr-1 and TNFa expression in these cells. Pretreatment of these cells with an inhibitor of MEK, p38 MAPK or JNK blocked the expression of Egr-1 and TNFa mRNAs by 10 Gy radiation. In contrast, inhibition of PI3K blocked the TNFa but not Egr-1 mRNA expression induced by radiation. Furthermore, cAMP response element-binding protein (CREB) linking to the transcription of Egr-1 was phosphorylated by radiation. Radiation-induced phosphorylation of CREB was blocked by pretreatment of each inhibitor. Our results suggest that the radiation-induced TNFa expression is mediated through the MEK, p38 MAPK, PI3K or JNK pathway via Egr-1 induction requiring activation of CREB in Jurkat cells. Further studies on mechanisms are in progress.第３１日本分子生物学会年会 第８１回日本生化学会大会 合同大