Interleukin-6 prevents NMDA-induced neuronal Ca2+ overload via suppression of IP3 receptors

The mechanism underlying interleukin-6 (IL-6) prevention of N-methyl-D-aspartate (NMDA)-induced neuronal Ca(2+) overload was explored at the profile of Ca(2+) channel receptors, including NMDA, inositol 1,4,5-trisphosphate and ryanodine receptors (NMDAR, IP3R and RyR, respectively).

Cerebellar granule neurons from 8-day-old rats were exposed to IL-6 (40 or 120 ng ml(-1)) for 8 days and stimulated with NMDA (100 μM) for 15 or 30 minutes.

NMDA evoked an acute and sustained enhancement of intracellular Ca(2+) fluorescence intensity in the entire 15-minute NMDA application period. IL-6 prevented the acute and sustained intracellular Ca(2+) elevation triggered by NMDA in a concentration-dependent manner. MK-801, an NMDAR antagonist, completely suppressed NMDA-evoked neuronal Ca(2+) overload in the absence or presence of IL-6. IP3R antagonist 2-APB lessened NMDA-evoked acute and sustained cytosolic Ca(2+) overload and IL-6 further reduced the acute 2-APB-dependent Ca(2+) component. Dissimilarly, after RyR antagonist DAN treatment, NMDA still induced an acute and sustained elevation of intracellular Ca(2+) levels, and the elevated Ca(2+) was significantly suppressed by IL-6. Moreover, IL-6 down-regulated NMDAR1 and IP3R1 but did not alter RyR2 expression.

The present results suggest that IL-6 suppresses NMDA-induced neuronal Ca(2+) overload by inhibiting NMDAR and IP3R activities.