We previously showed that survival signaling in TNF alpha-treated, human THP1-derived macrophages (TDMs) has an obligatory requirement for constitutive Ca2+ influx through a mechanism involving calmodulin/calmodulin kinase II (CAM/CAMKII). We also demonstrated that such requirement also applies to the protective actions of TNF alpha in murine bone marrow-derived macrophages (BMDMs) and that TRPC3 channels mediate constitutive Ca2+ influx. Using a pharmacological approach we here examined if in BMDMs, similarly to TDMs, TNF alpha-induced survival signaling also involves CAM/CAMKII. In BMDMs, TNF alpha induced rapid activation of the survival pathways NF kappa B, AKT and p38MAPK. All these routes were activated in a PI3K-dependent fashion. Activation of Ala and NF kappa B, but not that of p38MAPK, was abrogated by the CAM inhibitor W7, while KN-62, a CAMKII inhibitor, prevented activation of AKT and p38MAPK but not that of NF kappa B. Inhibition of CAM or CAMKII completely prevented the protective actions of TNF alpha. Our observations indicate that in BMDMs CAM and CAMKII have differential contributions to the components of TNF alpha-dependent survival signaling and underscore a complex interplay among canonical survival routes. These findings set a signaling framework to understand how constitutive Ca2+ influx couples to macrophage survival in BMDMs. (C) 2012 Elsevier Inc. All rights reserved.