TNFalpha reduces glutamate induced intracellular Ca(2+) increase in cultured cortical astrocytes.

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.