Calcineurin is the only Ca2+-dependent serine/threonine-specific protein phosphatase and is considered a potential regulator of many intracellular signaling events. In this study we identified a novel interaction between calcineurin and the 20S proteasome subunit PSMA6 that increased intracellular proteasomal activity. Using RAW 264.7 macrophage cells, we demonstrated that expression of inflammatory factors was induced by calcineurin, and suppressed by the calcineurin inhibitor FK506. We also found that these calcineurin-activated processes result from activation of NF-kappa B, and that the interaction of calcineurin with PSMA6 stimulates transcription by NF-kappa B via degradation of I kappa B by the ubiquitin-proteasome pathway. These findings indicate that calcineurin is required for expression of inflammatory factors, and reveal a novel process of calcineurin-mediated activation of NF-kappa B. (C) 2011 Elsevier Inc. All rights reserved.