Neuroprotection by transforming growth factor-β1 involves activation of nuclear factor-κB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways

Abstract

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-β1 (TGF-β1), 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-β1. 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-κβ is a target of TGF-β1 and which signaling pathways involved in the activation of NF-κβ are triggered by TGF-β1. We demonstrated that TGF-β1 increased the transcriptional activity of NF-κβ in cultured hippocampal neurons in a time- and concentration-dependent manner. Furthermore, TGF-β1 induced translocation of p65/NF-κβ to the nucleus and enhanced NF-κβ transcriptional activity in the presence of apoptotic stimuli. TGF-β1-mediated NF-κβ 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-β1. TGF-β1 produced a concomitant increase in the phosphorylations of Iκβ kinase (IKKα/β) and Iκβα with a subsequent degradation of Iκβα. Interestingly, the increased phosphorylation of IKKα/β and Iκβα was abrogated by wortmannin, but not by U0126, suggesting that PI3k/Akt and MAPK/Erk1,2 pathways triggered by TGF-β1 regulated the activation of NF-κβ through different mechanisms. Of note, wortmannin and U0126, as well as κβ-decoy DNA, abolished the anti-apoptotic effect of TGF-β1, corroborating the notion that both PI3k/Akt and MAPK/Erk1,2 pathways, and NF-κβ activity are necessary for the anti-apoptotic activity of TGF-β1.