Involvement of calmodulin and calmodulin kinase II in tumor necrosis factor alpha-induced survival of bone marrow derived macrophages.

ABSTRACT: We previously showed that survival signaling in TNF?-treated, human THP1-derived macrophages (TDMs) has an obligatory requirement for constitutive Ca(2+) 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? in murine bone marrow-derived macrophages (BMDMs) and that TRPC3 channels mediate constitutive Ca(2+) influx. Using a pharmacological approach we here examined if in BMDMs, similarly to TDMs, TNF?-induced survival signaling also involves CAM/CAMKII. In BMDMs, TNF? induced rapid activation of the survival pathways NF?B, AKT and p38MAPK. All these routes were activated in a PI3K-dependent fashion. Activation of AKT and NF?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?B. Inhibition of CAM or CAMKII completely prevented the protective actions of TNF?. Our observations indicate that in BMDMs CAM and CAMKII have differential contributions to the components of TNF?-dependent survival signaling and underscore a complex interplay among canonical survival routes. These findings set a signaling framework to understand how constitutive Ca(2+) influx couples to macrophage survival in BMDMs.

SUBMITTER: Tano JY 

PROVIDER: S-EPMC3485643 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature