摘要
Prevention of neuronal apoptosis has been introduced as a new therapeutic strategy for neurodegenerative disorders. We have previously reported anti-apoptotic effects of transforming growth factor-946;1 (TGF-946;1), a multifunctional cytokine, in models of cerebral ischemia and in cultured neurons and recently focused on the mechanisms underlying the anti-apoptotic effect of TGF-946;1. The anti-apoptotic transcriptional factor nuclear factor kappa B (NF-κB) shows high impact in the cell survival function of multiple cytokines and growth factors. The present study explored whether NF-κ946; is a target of TGF-946;1 and which signaling pathways involved in the activation of NF-κ946; are triggered by TGF-946;1. We demonstrated that TGF-946;1 increased the transcriptional activity of NF-κ946; in cultured hippocampal neurons in a time- and concentration-dependent manner. Furthermore, TGF-946;1 induced translocation of p65/NF-κ946; to the nucleus and enhanced NF-κ946; transcriptional activity in the presence of apoptotic stimuli. TGF-946;1-mediated NF-κ946; activation was blocked by wortmannin and U0126, indicating the involvement of both phosphatidylinositol-3-OH kinase (PI3k)/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (Erk)1,2 pathways in the action of TGF-946;1. TGF-946;1 produced a concomitant increase in the phosphorylations of Iκ946; kinase (IKKα/946;) and Iκ946;α with a subsequent degradation of Iκ946;α. Interestingly, the increased phosphorylation of IKKα/946; and Iκ946;α was abrogated by wortmannin, but not by U0126, suggesting that PI3k/Akt and MAPK/Erk1,2 pathways triggered by TGF-946;1 regulated the activation of NF-κ946; through different mechanisms. Of note, wortmannin and U0126, as well as κ946;-decoy DNA, abolished the anti-apoptotic effect of TGF-946;1, corroborating the notion that both PI3k/Akt and MAPK/Erk1,2 pathways, and NF-κ946; activity are necessary for the anti-apoptotic activity of TGF-946;1.