We showed previously that calcineurin B subunit (CnB) could inhibit S180 solid tumor growth in mice and prolong the survival of mice bearing H22 ascites tumors, but the underlying antitumor mechanism remained unclear. Here, we report that the calcineurin B subunit binds to CD11b on RAW264.7 macrophages and induces TRAIL expression and NF-kappa B activation in a dose and time dependent manner, and that CnB-induced TRAIL expression and NF-kappa B activation are both dependent on this CD11 b. Furthermore. CnB-induced TRAIL expression is mediated by NF-kappa B. These findings reveal a novel signaling pathway (CnB-CD11b-NF-kappa B-TRAIL) regulating TRAIL expression and may help to understand the roles of the calcineurin B subunit in the regulation of innate immunity. (C) 2011 Elsevier Inc. All rights reserved.