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TNFalpha reduces glutamate induced intracellular Ca(2+) increase in cultured cortical astrocytes
H Köller1, M Trimborn, H von Giesen
1Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, P.O. Box 101007, D-40001 Düsseldorf, Germany. koellerh@uni-duesseldorf.de
Abstract:
The proinflammatory cytokine TNFalpha is locally released during various inflammatory CNS diseases and high cerebrospinal fluid (CSF) titers of TNFalpha were found in meningitis patients. We know from previous studies that TNFalpha also depolarizes astrocytes by reducing their inwardly rectifying K+ currents. We have now investigated the effect of TNFalpha on the glutamate induced intracellular Ca2+ increase in astrocytes, a process which seems to be involved in glial mediated modulation of neuronal synaptic transmisssion. Incubation with TNFalpha (50-1000 U/ml for 60 min) reduces the glutamate induced intracellular Ca2+ increase in astrocytes but not in neurons and this seems to be a phenomenon secondary to the TNFalpha induced depolarization. While other proinflammatory cytokines (interleukin 1beta, IL-2, IL-6) did not interfere with the astrocytic glutamate response, incubation in CSF from septic meningitis patients (CSF-SM) also reduced the glutamate induced intracellular Ca2+ increase. The application of a neutralizing anti-TNFalpha antibody to the CSF-SM prior to cell incubation partially restored the glutamate response. Our data suggest that inflammatory molecules such as TNFalpha impair astrocytes' response to glutamate and this may indirectly affect neuronal synaptic transmission.
Insights
Tumor necrosis factor-alpha (TNFalpha) impairs astrocyte responses to glutamate, potentially affecting neuronal communication in brain inflammation. This finding highlights TNFalpha
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) is elevated in cerebrospinal fluid (CSF) during CNS inflammatory diseases like meningitis.
- TNFalpha is known to depolarize astrocytes by reducing inwardly rectifying K+ currents.
- Astrocytes play a role in modulating neuronal synaptic transmission.
Purpose of the Study:
- To investigate the effect of TNFalpha on glutamate-induced intracellular Ca2+ increase in astrocytes.
- To determine if TNFalpha's effect on astrocytes is secondary to depolarization.
- To assess the impact of TNFalpha and other cytokines on astrocytic glutamate response.
Main Methods:
- Astrocytes and neurons were incubated with TNFalpha (50-1000 U/ml for 60 min).
- Glutamate-induced intracellular Ca2+ increases were measured in the presence and absence of TNFalpha.
- Cerebrospinal fluid (CSF) from septic meningitis patients (CSF-SM) was used to assess its effect on astrocytic glutamate response.
- Neutralizing anti-TNFalpha antibody was applied to CSF-SM before cell incubation.
Main Results:
- TNFalpha significantly reduced glutamate-induced intracellular Ca2+ increase in astrocytes, but not in neurons.
- This reduction in astrocytes appears secondary to TNFalpha-induced depolarization.
- Other proinflammatory cytokines (IL-1beta, IL-2, IL-6) did not affect the astrocytic glutamate response.
- CSF from septic meningitis patients also reduced the glutamate response in astrocytes.
- A neutralizing anti-TNFalpha antibody partially restored the glutamate response in astrocytes incubated with CSF-SM.
Conclusions:
- TNFalpha impairs astrocyte response to glutamate, likely via depolarization.
- This impairment of astrocyte function by TNFalpha may indirectly affect neuronal synaptic transmission.
- TNFalpha is a key inflammatory mediator impacting glial cell responses in CNS diseases.