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  • 1
    Electronic Resource
    Electronic Resource
    Interleukin-1β and Tumor Necrosis Factor-α Induce Expression of α1-Antichymotrypsin in Human Astrocytoma Cells by Activation of Nuclear Factor-κB (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The protease inhibitor α1-antichymotrypsin (ACT) has been suggested to be involved in the etiology of Alzheimer's disease (AD). Increased levels of ACT have been found in serum and brains of AD patients, and ACT has been proposed to regulate β-amyloid fibril formation in vitro. To gain insight into the regulation of ACT in the brain, we investigated the signal transduction pathways involved in ACT gene expression and protein synthesis in the human astrocytoma cell line U373. This cell line has previously been shown to respond with strong ACT synthesis on stimulation with interleukin-1β (IL-1β) or tumor necrosis factor-α (TNFα). Here, we describe that both IL-1β and TNFα activate the transcription factor nuclear factor-κB (NF-κB) via production of reactive oxygen intermediates resulting in ACT expression. In addition, we show that neither protein kinase C nor protein kinase A is involved in IL-1β- or TNFα-induced ACT expression. These results suggest that activation of NF-κB may be one possible cause of increased ACT levels in AD and provide a basis for the development of drugs used for the modulation of inflammatory processes occurring in AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67052039.x
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  • 2
    Electronic Resource
    Electronic Resource
    Interleukin-1β Uses Common and Distinct Signaling Pathways for Induction of the Interleukin-6 and Tumor Necrosis Factor α Genes in the Human Astrocytoma Cell Line U373 (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cytokines are involved in the etiology of different disorders of the CNS. For a better understanding of their pathogenic role, we analyzed signal transduction pathways mediating the interleukin (IL)-1β-induced synthesis of IL-6 and tumor necrosis factor α (TNFα) in the human astrocytoma cell line U373 MG. Both protein kinase C and reactive oxygen intermediates (ROIs) were involved in IL-6 and TNFα gene expression by IL-1β. In contrast, protein tyrosine kinases were only necessary for expression of the IL-6 gene. Whereas activation of protein kinase A was able to induce expression of the IL-6 gene, it did not induce TNFα gene expression and was not involved in IL-1β-induced IL-6 and TNFα gene expression. Activation of the transcription factor nuclear factor-κB by IL-1β involved ROIs, whereas the IL-1β-induced activation of the transcription factor AP-1 was mediated via protein kinase C. Our findings provide the basis for the development of specific drugs for the treatment of disorders of the CNS in which cytokines play a pathogenic role.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66041496.x
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  • 3
    Electronic Resource
    Electronic Resource
    Adenosine A2b Receptors Mediate an Increase in Interleukin (IL)-6 mRNA and IL-6 Protein Synthesis in Human Astroglioma Cells (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The cytokine interleukin (IL)-6 has recently been demonstrated to play a role in the pathology of Alzheimer's disease (AD). The mechanisms leading to increased IL-6 levels in brains of AD patients are still unknown. Because in experimental animals ischemia increases both the level of cytokines and the extracellular concentrations of adenosine in the brain, we hypothesized that these two phenomena may be functionally connected and that adenosine might increase IL-6 gene expression in the brain. Here we show that the mixed A1 and A2 agonist 5′-(N-ethylcarboxamido)adenosine (NECA) induces an increase in IL-6 mRNA levels and protein synthesis in the human astrocytoma cell line U373 MG. The A1-specific agonists R-phenylisopropyladenosine and cyclopentyladenosine are much less potent, and the A2a-specific agonist CGS-21680 shows only marginal effects. Increased levels of mRNA are already found within 30 min after NECA treatment. The A2a-selective antagonists 8-(3-chlorostyryl)caffeine and KF17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine], which have also some antagonistic properties at A2b receptors, and the nonspecific adenosine antagonist 8-phenyltheophylline were equipotent at inhibiting the NECA-induced increase in IL-6 protein synthesis, whereas the specific A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine is much less potent. The results indicate that adenosine A2b receptors participate in the regulation of the IL-6 gene in astrocytoma cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66041426.x
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  • 4
    Electronic Resource
    Electronic Resource
    Prostaglandin E2 Induces Interleukin-6 Synthesis in Human Astrocytoma Cells (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD) and prion diseases. Nonsteroidal antiinflammatory drugs (NSAIDs), potent inhibitors of PG synthesis, appear to be beneficial in the treatment of AD. To assess whether PGs are able to induce IL-6 synthesis in cells of the CNS, IL-6 mRNA and protein syntheses were measured in a human astrocytoma cell line after stimulation with different PGs. PGE1 and PGE2, but not PGD2 and PGF2α, led to a rapid and transient induction of IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1β-induced IL-6 mRNA synthesis. These results are discussed with respect to the participation of PGs in neurodegenerative diseases (and its inhibition by NSAIDs) by affecting cytokine expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68020704.x
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  • 5
    Electronic Resource
    Electronic Resource
    Substance P and Histamine Induce Interleukin-6 Expression in Human Astrocytoma Cells by a Mechanism Involving Protein Kinase C and Nuclear Factor-IL-6 (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 70 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1β, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1β-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1β-induced IL-6 expression required the transcription factor nuclear factor-κB (NF-κB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-κB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70041577.x
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  • 6
    Electronic Resource
    Electronic Resource
    Interleukin-1β Induces Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Human Neuroblastoma Cells (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Prostaglandins (PGs), which are generated by the enzymatic activity of cyclooxygenase (COX)-1 and -2, modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the neuronal induction of COX-2 has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). The regulation of COX expression in neuronal cells is only partly understood and has been mainly linked to synaptic activity. In pathophysiological situations, however, cytokines may be potent stimulators of neuronal COX expression. Here we show that interleukin (IL)-1β induces COX-2 mRNA and protein synthesis and the release of PGE2 in the human neuroblastoma cell line SK-N-SH. We further demonstrate that both a free radical scavenger and an inhibitor of p38 mitogen-activated protein kinase (MAPK) reduce IL-1β-induced synthesis of COX-2. IL-1β induces p38 MAPK phosphorylation and activation of the nuclear factor-κB independently from each other. Our data suggest that IL-1β-induced COX-2 expression in SK-N-SH cells is regulated by different mechanisms, presumably involving mRNA transcription and mRNA stability. The ability of p38 MAPK to augment COX-2 expression in human neuroblastoma cells, as shown here, suggests that p38 MAPK may be involved in neuronal expression of COX-2 in AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0752020.x
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  • 7
    Electronic Resource
    Electronic Resource
    Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein kinase C ɛ resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 93 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Serotonin [5-hydroxytryptamine (5-HT)] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes. Previously, it has been demonstrated that 5-HT may induce interleukin (IL)-6 expression in primary rat hippocampal astrocytes. The present study was undertaken to investigate the molecular pathways underlying this induction of IL-6 synthesis. As a model system, we used the human astrocytoma cell line U373 MG, which synthesizes IL-6 upon stimulation with various inducers. 5-HT dose- and time-dependently induced IL-6 protein synthesis. We identified several 5-HT receptors to be expressed on U373 MG cells, including the 5-HT1D, 5-HT2A, 5-HT3 and 5-HT7 receptors. In this report, we show that the 5-HT-induced IL-6 release is mediated by the 5-HT7 receptor based on several agonist/antagonists that were used. 5-HT-induced IL-6 synthesis is inhibited by the partially selective 5-HT7 receptor antagonist, pimozide, and the selective antagonist SB269970. Furthermore, IL-6 synthesis was induced by the 5-HT7 receptor agonist carboxamidotryptamin. In addition, we found p38 MAPKs and protein kinase C (PKC) ɛ to be involved in 5-HT-induced IL-6 synthesis as specific inhibitors of these enzymes (SB202190 and RO-31-8425, respectively) blocked 5-HT-induced IL-6 synthesis. Furthermore, 5-HT mediated the phosphorylation of both p38 MAPK as well as the PKC ɛ isoform. The p42/44 MAPKs, however, were not involved in 5-HT-induced IL-6 synthesis. This study shows, for the first time, a central role of 5-HT7 receptor linked to p38 MAPK and PKC ɛ for the induction of cytokine synthesis in astrocytic cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03079.x
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  • 8
    Electronic Resource
    Electronic Resource
    1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline-induced apoptosis in the human neuroblastoma cell line SK-N-SH (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 91 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Trichloroethylene, a common industrial solvent and a metabolic precursor of chloral hydrate, occurs widely in the environment. Chloral hydrate, which is also used as a hypnotic, has been found to condense spontaneously with tryptamine, in vivo, to give rise to a highly unpolar 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) that has a structural analogy to the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Earlier studies have revealed the relative permeability of the molecule through the blood–brain barrier and its ability to induce Parkinson-like symptoms in rats. In this study, we report that TaClo induces an apoptotic pathway in the human neuroblastoma cell line, SK-N-SH, involving the translocation of mitochondrial cytochrome c to the cytosol and activation of caspase 3. TaClo-induced apoptosis shows considerable differences from that mediated by other Parkinson-inducing agents such as MPTP, rotenone and manganese. Although it is not clear if the clinically administered dosage of chloral hydrate or the relatively high environmental levels of trichloroethylene could lead to an onset of Parkinson's disease, the spontaneous in vivo formation of TaClo and its pro-apoptotic properties, as shown in this report, should be considered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02710.x
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  • 9
    Electronic Resource
    Electronic Resource
    Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 86 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The neuropeptide substance P (SP) has been hypothesized to be involved in the etiopathology of affective disorders. This hypothesis is based on the findings that neurokinin-1-receptor antagonists have antidepressant effects in depressed patients and that SP may worsen mood. In this study, we investigated the effect of the mood-stabilizing agents valproic acid (VPA), carbamazepine, and lithium on SP-induced gene expression. As a model system, we used primary rat astrocytes and human astrocytoma cells, which both express functional SP-receptors and, upon stimulation with SP, synthesize interleukin-6 (IL-6), a cytokine which has been shown to be elevated during the acute depressive state. We found that VPA dose-dependently inhibited SP-induced IL-6 synthesis which was seen with pre-incubation periods of 30 min, 3, 7 and 14 days, whereas carbamazepine and lithium showed no inhibitory effect. The inhibitory effect of VPA was not mediated by inhibition of the stress-regulated kinases p38 and p42/44 (Erk1/2) but by inhibition of protein kinase C epsilon activation. Furthermore, VPA down-regulated the expression of the substance P receptor (neurokinin(NK)-1-receptor) as assessed by real-time PCR. Whether both mechanisms contribute to the mood-stabilizing properties of VPA has to be evaluated in further studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01802.x
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  • 10
    Electronic Resource
    Electronic Resource
    Synergistic inhibitory effect of ascorbic acid and acetylsalicylic acid on prostaglandin E2 release in primary rat microglia (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 86 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Ascorbic acid (vitamin C) has been suggested to protect cerebral tissue in a variety of pathophysiological situations such as head trauma, ischemia or Alzheimer's disease. Most of these protective actions have been attributed to the antioxidative capacity of ascorbic acid. Besides the presence of elevated levels of oxygen radicals, prostaglandins produced by neurones and microglial cells seem to play an important role in prolonged tissue damage. We investigated whether ascorbic acid alone inhibits prostaglandin E2 (PGE2) synthesis and may augment the inhibitory effect of acetylsalicylic acid on prostaglandin synthesis. Ascorbic acid dose-dependently inhibited PGE2 synthesis in lipopolysaccharide-treated primary rat microglial cells (IC50 = 3.70 µm). In combination with acetylsalicylic acid (IC50 = 1.85 µm), ascorbic acid augmented the inhibitory effect of acetylsalicylic acid on PGE2 synthesis (IC50 = 0.25 µm in combination with 100 µm ascorbic acid). Ascorbic acid alone or in combination with acetylsalicylic acid did not inhibit cyclooxygenase-2 (COX-2) protein synthesis but inhibited COX-2 enzyme activity. Our results show that ascorbic acid and acetylsalicylic acid act synergistically in inhibiting PGE2 synthesis, which may help to explain a possible protective effect of ascorbic acid in various brain diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01822.x
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