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

We report induction of TNF-α via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-α mRNA, protein and TNF-α 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-α promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-α promoter. Given proposed functions of TNF-α 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. © 2006 Elsevier Inc. All rights reserved.This work was supported by grant 08.5/0039.1/2003 from the Comunidad Autónoma de Madrid (CAM) to E. Cano and by grants to J.M. Redondo from the Ministerio de Ciencia y Tecnología (SAF 2003-02920), the RECAVA programme of the Ministerio de Sanidad y Consumo, the European Union LSHM-CT-2004-005033 (EICOSANOX) and the Fundación La Marato (TV3). A. Canellada was supported by a fellowship from the Ministerio de Educación y Ciencia and the Fundación Carolina of Spain. E. Cano is a recipient of a Ramon y Cajal contract from the Ministerio de Educación y Ciencia.Peer Reviewe