Tumor Necrosis Factor α Inhibits Glutamate Uptake by Primary Human Astrocytes

Fine, Steven M.; Angel, Robert A.; Perry, Seth W.; Epstein, Leon G.; Rothstein, Jeffrey D.; Dewhurst, Stephen; Gelbard, Harris A.

doi:10.1074/jbc.271.26.15303

Cited by 303 publications

(187 citation statements)

References 28 publications

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“…If an excitotoxic mechanism is operating in HIV-1 infection, note that PAF is known to enhance excitatory transmission [27]. TNF-␣ [28] and arachidonic acid [29] block the crucial high-affinity glutamate uptake of astrocytes at synaptic clefts. Restricted HIV infection of astrocytes and over-expression of regulatory proteins such as tat or nef may further compromise vital astrocyte functions [30].…”

Section: Excitotoxic Injury In the Developing Nervous Systemmentioning

confidence: 99%

“…Attempting to reduce levels of TNF-␣ in brain would be a cornerstone of therapy because Tat can up-regulate TNF-␣ production in glial cells [51,52] and TNF-␣ in turn can induce neuronal apoptosis by a mechanism that is independent of NF-B activation but involves activation of non-NMDA receptors [21,32], as well as reduce glutamate uptake [28]. Agents are presently available to decrease TNF-␣ production at the transcriptional level and to bind to TNF-␣ (soluble receptor fragments), but delivery across the blood-brain barrier may limit their efficacy.…”

Section: Therapeutic Strategies For Hiv-1 Infection In the Developingmentioning

confidence: 99%

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HIV-1-induced neuronal injury in the developing brain

Epstein

Gelbard

1999

Journal of Leukocyte Biology

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HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor ␣ (TNF-␣) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide ''neuroprotection'' from excitotoxic neuronal injury. J. Leukoc. Biol. 65: 453-457; 1999.

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Section: Excitotoxic Injury In the Developing Nervous Systemmentioning

confidence: 99%

Section: Therapeutic Strategies For Hiv-1 Infection In the Developingmentioning

confidence: 99%

HIV-1-induced neuronal injury in the developing brain

Epstein

Gelbard

1999

Journal of Leukocyte Biology

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“…The excitatory amino acid transporter 2 (EAAT2) prevents glutamate toxicity by removing excess glutamate from the synaptic cleft. Treatment with TNF-a down-regulates EAAT2 mRNA and protein and also inhibits EAAT2-Prom activity in primary human fetal astrocytes (18,19) The primary pathway by which TNF-a suppresses EAAT2 expression is by activating NF-nB (19,20) that binds to the EAAT2 promoter and inhibits its activity. Interestingly, ectopic expression of AEG-1 also inhibits EAAT2 promoter activity.…”

Section: Introductionmentioning

confidence: 99%

Activation of the Nuclear Factor κB Pathway by Astrocyte Elevated Gene-1: Implications for Tumor Progression and Metastasis

Emdad¹,

Sarkar²,

Su³

et al. 2006

Cancer Research

258

355

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Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1-and tumor necrosis factor A (TNF-A)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor KB (NF-KB), a TNF-A downstream signaling component, is associated with several human illnesses, including cancer, and NF-KB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-KB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-KB. The NF-KB activation induced by AEG-1 corresponded with degradation of IKBA and nuclear translocation of p65 that resulted in the induction of NF-KB downstream genes. Infection with an adenovirus expressing the mt32IKBA superrepressor (Ad.IKBA-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-A treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-KB. Our findings suggest that activation of NF-KB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.

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“…Thus, there is a clear connection between improper uptake capacity and CNS damage. Products of HIV infection, gp120 and TNF-α, inhibit glutamate uptake by astrocytes (148,149). Compounding these effects, HIV-1 has been shown to downregulate glutamate transporter EAAT2, causing disruptions in glutamate uptake (149).…”

Section: Impairment Of Astrocytes In Hadmentioning

confidence: 99%

“…Further, G-protein linked mGlu receptors may cause increased intracellular Ca 2+ , leading to glutamate release from astrocytes (150). Astrocytic release of glutamate has been shown to be stimulated by arachidonic acid, TNF-α, and CXCL12 (50,148,151). In addition, numerous studies have indicated a potential for the reversal of glutamate uptake, causing further glutamate dumping (152,153).…”

Section: Impairment Of Astrocytes In Hadmentioning

confidence: 99%

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

Erdmann¹,

Whitney²,

Zheng³

2006

Clinical Neuroscience Research

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HIV-1 Associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis.

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Tumor Necrosis Factor α Inhibits Glutamate Uptake by Primary Human Astrocytes

Cited by 303 publications

References 28 publications

HIV-1-induced neuronal injury in the developing brain

HIV-1-induced neuronal injury in the developing brain

Activation of the Nuclear Factor κB Pathway by Astrocyte Elevated Gene-1: Implications for Tumor Progression and Metastasis

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

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