Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway

FTY720 is a novel immunosuppressive drug derived from a metabolite from Isa ria sinclairii that is known to induce apoptosis of rat splenic T cells. In this study, we examined the intracellular signaling pathway triggered by F TY720, Treatment of human Jurkat T lymphocytes with FTY720-induced apoptosi s characterized by DNA fragmentation. The same treatment induced activation of protein kinases such as c-Jun NH2-terminal kinase (JNK), p38/CSBP (CSAI D-binding protein), and a novel 36-kDa myelin basic protein (MBP) kinase, b ut not extracellular signal-regulated kinase (ERK), Pretreatment of Jurkat cells with DEVD-CHO blocked FTY720-induced DNA fragmentation as well as the activation of p38/CSBP, However, DEVD-CHO treatment failed to inhibit FTY7 20-induced activation of JNK and the 36-kDa MBP kinase, We have also demons trated that activation of the ERK signaling pathway completely suppressed t he FTY720-induced apoptotic process including activation of caspase 3 and a ctivation of JNK and the 36-kDa MBP kinase, Furthermore, transient expressi on of constitutively active mitogen-activated protein kinase/ ERK kinase (M EK) protected the cells from FTY720-induced cell death. The effect of MEK w as canceled by coexpression of a mitogen-activated protein kinase phosphata se, CL100. These results indicate that JNK and p38 pathways are differentia lly regulated during FTY720-induced apoptosis and that activation of ERK pa thway alone is sufficient to cancel the FTY720-induced death signal.