Calcium-dependent expression of TNF-alpha in neural cells is mediated by the calcineurin/NFAT pathway.

We report induction of TNF-alpha via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-alpha mRNA, protein and TNF-alpha gene promoter activity was induced by co-stimulation with phorbol ester and either calcium ionophore A23187 or the L-type Voltage Gated Calcium Channel agonist Bay K 8644. Pre-treatment with calcineurin inhibitors CsA or FK506 inhibited the dominant calcium-dependent component of this induction, limiting it to the level achieved with phorbol ester alone. Promoter activation by Bay was abolished by nifedipine, a specific inhibitor of L-type Voltage Gated Calcium Channels. Exogenous NFAT protein transactivated the TNF-alpha promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-alpha promoter. Given proposed functions of TNF-alpha in spatial learning, memory and the pathogenesis of neurodegenerative diseases, the data presented suggest an important role for calcineurin/NFAT signaling in these key neurological processes.