Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-alpha: possible involvement of multiple signal transduction and beta-catenin/T-cell factor.
Cerebrospinal fluid prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with Alzheimer's disease (AD), which suggests that they are involved in neurodegeneration. We previously reported that TNF-alpha derived from human macrophages, in response to beta-amyloid or amyloidogenic C-terminal peptide, is a main mediator of inflammatory neurotoxicity. In a continuation of this work, the present study investigated the direct effect of PGE2, one of the major prostaglandins produced in the brain, on cell viability in SH-SY5Y neuronal cells treated with TNF-alpha. PGE2 did not promote neurotoxicity, but rather had a strong protective effect against TNF-alpha by ameliorating TNF-alpha-induced apoptosis and also by rescuing the intracellular level of beta-catenin, a key transducer of the Wnt signaling pathway. PGE2-mediated stabilization of beta-catenin was accompanied by T-cell factor/lymphoid enhancer factor (Tcf/Lef)-mediated transcriptional activation, which was followed by an increase in the cyclinD1 level. Pharmacological studies provided further evidence supporting the notion that PGE2-mediated neuroprotection against TNF-alpha involves the stimulation of Tcf/Lef signaling through EP1-, EP2-, and EP4-mediated increases of beta-catenin in SH-SY5Y cells. In addition, this PGE2 effect appears to be dependent on the activation of protein kinase A, phosphatidylinositol 3-kinase, phospholipase C, and to a lesser extent protein kinase C. Thus, the molecular mechanism governing the inhibitory effect of PGE2 against TNF-alpha may involve the activation and cross talk of multiple signal transduction and play an important role in regulating the survival of neurons during the neurotoxic inflammatory response associated with neurodegenerative diseases including AD.
Lee
Eun Ok
EO
Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University, 911-1, Mok-6-dong, Yangcheonku, Seoul, 158-710, South Korea.
Shin
Yoo Jung
YJ
Chong
Young Hae
YH
D000544:Alzheimer Disease / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000187:drug effects* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000633:toxicity; D051821:Lymphoid Enhancer-Binding Factor 1; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000276:immunology; D018696:Neuroprotective Agents / Q000276:immunology / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D011494:Protein Kinases / Q000187:drug effects / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000187:drug effects* / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010738:Type C Phospholipases / Q000187:drug effects / Q000276:immunology; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D051821:Lymphoid Enhancer-Binding Factor 1; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018078:Receptors, Prostaglandin E; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D019938:Cyclin D1; D011494:Protein Kinases; D010738:Type C Phospholipases; D015232:Dinoprostone