Neuroprotection by transforming growth factor-beta1 involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1,2 signaling pathways.
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-beta1 (TGF-beta1), 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-beta1. The anti-apoptotic transcriptional factor nuclear factor kappa B (NF-kappaB) shows high impact in the cell survival function of multiple cytokines and growth factors. The present study explored whether NF-kappabeta is a target of TGF-beta1 and which signaling pathways involved in the activation of NF-kappabeta are triggered by TGF-beta1. We demonstrated that TGF-beta1 increased the transcriptional activity of NF-kappabeta in cultured hippocampal neurons in a time- and concentration-dependent manner. Furthermore, TGF-beta1 induced translocation of p65/NF-kappabeta to the nucleus and enhanced NF-kappabeta transcriptional activity in the presence of apoptotic stimuli. TGF-beta1-mediated NF-kappabeta 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-beta1. TGF-beta1 produced a concomitant increase in the phosphorylations of Ikappabeta kinase (IKKalpha/beta) and Ikappabetaalpha with a subsequent degradation of Ikappabetaalpha. Interestingly, the increased phosphorylation of IKKalpha/beta and Ikappabetaalpha was abrogated by wortmannin, but not by U0126, suggesting that PI3k/Akt and MAPK/Erk1,2 pathways triggered by TGF-beta1 regulated the activation of NF-kappabeta through different mechanisms. Of note, wortmannin and U0126, as well as kappabeta-decoy DNA, abolished the anti-apoptotic effect of TGF-beta1, corroborating the notion that both PI3k/Akt and MAPK/Erk1,2 pathways, and NF-kappabeta activity are necessary for the anti-apoptotic activity of TGF-beta1.
Zhu
Y
Y
Institut fuer Pharmakologie und Toxikologie, Philipps-Universitaet, Ketzerbach 63, D-35032 Marburg, Germany. zhu@mailer.uni-marburg.de
Culmsee
C
C
Klumpp
S
S
Krieglstein
J
J
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011916:Rats, Inbred F344; D019311:Staurosporine / Q000633:toxicity; D050863:Synaptotagmin I; D050857:Synaptotagmins; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine; D050863:Synaptotagmin I; D050857:Synaptotagmins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; C494920:Akt1 protein, rat