Abstract
Increasing evidence supports a role for cytokines as chemical signals in the CNS, either under normal conditions or in the pathologic state. CNS levels of the cytokine interleukin-6 (IL-6) are known to be elevated in several diseases associated with developmental disorders and may contribute to the pathological state. To investigate the potential role of IL-6 in such disorders, neuronal effects of IL-6 were examined during development using an in vitro model system, cultured rat cerebellar granule neurons. The cultures were prepared from 8 d postnatal rat pups and exposed chronically to IL-6 (5 ng/ml) by addition to the culture medium. Neuronal effects of IL-6 were assessed by a comparison of calcium signals produced in control and IL-6 treated neurons by the glutamate receptor agonists NMDA and domoate and by K+ depolarization. IL-6 treatment significantly enhanced the response to NMDA and altered the developmental pattern of NMDA sensitivity, whereas only minor changes were observed for the response to domoate and K+. Reducing extracellular calcium and depleting intracellular stores significantly decreased the amplitude of the response to NMDA in control and IL-6 treated neurons. However, the IL-6 treated neurons were significantly more sensitive to these treatments than control neurons. These results suggest that elevated levels of IL-6 can significantly alter CNS neuron development and response to excitatory transmitters, and that IL-6 pretreatment selectively enhances the intracellular calcium responses to NMDA by altering the relative contribution of extracellular calcium influx and release of calcium from stores to the calcium signal.
