Neuronal survival activity of S100ββ is enhanced by calcineurin inhibitors and requires activation of NF-κB

S100 beta beta is a calcium binding, neurotrophic protein produced by nonneuronal cells in the nervous system. The pathway by which it enhances neuronal survival is unknown. Here we show that S100 beta beta enhances survival of embryonic chick forebrain neurons in a dose-dependent manner. In the presence of suboptimal amounts of S100 beta beta, neuronal survival is enhanced by the immunosuppressants FK506 and cyclosporin A at concentrations that inhibit calcineurin, which is present in these cells. Rapamycin, an immunosuppressant that does not inhibit calcineurin, did not enhance cell survival, Cypermethrin, a direct and highly specific calcineurin inhibitor, mimicked the immunophilin ligands in its neurotrophic effect. None of the drugs stimulated neuronal survival in the absence of S100 beta beta, In the presence of suboptimal amounts of S100 beta beta, FK506, cyclosporin A, and cypermethrin (but not rapamycin) also increased NF-kappa B activity, as measured by immunofluorescence of cells stained with antibody to the active subunit (p65) and by immunoblotting of nuclear extracts. Antioxidant and glucocorticoid inhibitors of NF-kappa B decreased both the amount of active NF-kappa B and the survival of neurons caused by S100 beta beta alone or in the presence of augmenting drugs. We conclude that S100 beta beta enhances the survival of chick embryo forebrain neurons through the activation of NF-kappa B.