Using whole-cell patch-clamp recordings, this study investigated the effects of interleukin-2 (IL-2) on N-methyl-D-aspartate (NMDA) receptor-mediated currents (I-NMDA) in rat cultured hippocampal neurons and human embryonic kidney (HEK) 293 cells expressing recombinant NMDA receptors. We found that IL-2 (0.01-1 ng/ml) immediately and significantly decreased peak INMDA in cultured neurons. Interestingly, the peak INMDA induced in HEK 293 cells was also inhibited by IL-2. We also found that IL-2 differentially decreased the peak amplitudes of NR2A- and NR2B-containing NMDA receptor-mediated currents (I-NR2A and I-NR2B) by 54 +/- 5% and 30 +/- 4%, respectively. These results provide new evidence that IL-2 induces rapid inhibition of peak currents of NMDA receptor-mediated responses with possible NR1/NR2A and NR1/NR2B subtype-differentiation, and suggest that the inhibition is mediated by direct interaction between IL-2 and NMDA receptors. (c) 2006 Elsevier Inc. All rights reserved.