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The Journal of Neuroscience, May 1, 2001, 21(9):3104-3112

Interleukin-10 Prevents Glutamate-Mediated Cerebellar Granule Cell Death by Blocking Caspase-3-Like Activity

Alessia Bachis^{1, 4}, Anna M. Colangelo¹, Stefano Vicini², Pylord P. Doe², Maria A. De Bernardi³, Gary Brooker³, and Italo Mocchetti^{1, 4}

Departments of ¹ Neuroscience and ² Physiology, Georgetown University, Washington, DC 20007, ³ Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, and ⁴ University of Cagliari, School of Pharmacy, 09124 Cagliari, Italy

Interleukin-10 (IL-10) has been shown to reduce neuronal degeneration after CNS injury. However, the molecular mechanisms underlying the neuroprotective properties of this cytokine are still under investigation. Glutamate exacerbates secondary injury caused by trauma. Thus, we examined whether IL-10 prevents glutamate-mediated cell death. We used rat cerebellar granule cells in culture because these neurons undergo apoptosis upon exposure to toxic concentrations of glutamate (100-500 µM) or NMDA (300 µM). Pretreatment of cerebellar granule cells with IL-10 (1-50 ng/ml) elicited a dose- and time-dependent reduction of glutamate-induced excitotoxicity. Most importantly, IL-10 reduced the number of apoptotic cells when added to the cultures together or 1 hr after glutamate. Using patch-clamping and fluorescence Ca²⁺ imaging techniques, we examined whether IL-10 prevents glutamate toxicity by blocking the function of NMDA channel. IL-10 failed to affect NMDA channel properties and to reduce NMDA-mediated rise in intracellular Ca²⁺. Thus, this cytokine appears to prevent glutamate toxicity by a mechanism unrelated to a blockade of NMDA receptor function. Various proteases, such as caspase-3, and transcription factors, such as nuclear factor B (NF-B), have been proposed to participate in glutamate-mediated apoptosis. Thus, we examined whether IL-10 modulates the activity of these apoptotic markers. IL-10 blocked both the glutamate-mediated induction of caspase-3 as well as NF-B DNA binding activity, suggesting that the neuroprotective properties of IL-10 may rely on its ability to block the activity of proapoptotic proteins.

Key words: apoptosis; Ca²⁺; caspase-3; EAA; IL-10; NF-B; NMDA receptors

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2193104-09$05.00/0

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