Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine that is primarily produced by microglia in the brain. IL-1β inhibits N-methyl-d-aspartate (NMDA)-induced outward currents (INMDA-OUT) through IL-1 type I receptor (IL-1RI) in hippocampal CA1 neurons (Zhang, R., Yamada, J., Hayashi, Y., Wu, Z, Koyama, S., Nakanishi, H., 2008. Inhibition of NMDA-induced outward currents by interleukin-1β in hippocampal neurons, Biochem. Biophys. Res. Commun. 372, 816-820). Although IL-1RI is associated with mitogen-activated protein kinases, their involvement in the effect of IL-1β on INMDA-OUT remains unclear. In the present study, we demonstrate that IL-1β caused activation of p38 mitogen-activated protein kinase and that the p38 inhibitor SB203580 significantly blocked the effect of IL-1β on INMDA-OUT in hippocampal CA1 neurons. Furthermore, the intracellular perfusion of active recombinant p38α significantly decreased the mean amplitude of INMDA-OUT. In neurons prepared from inflamed hippocampus, the mean amplitude of INMDA-OUT was significantly reduced. In the inflamed hippocampus, IL-1β and IL-1RI were expressed mainly in microglia and neurons, respectively. These results suggest that IL-1β increases the excitability of hippocampal CA1 neurons in the p38-dependent inhibition of INMDA-OUT.
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