Cyclosporine A Induces Nerve Growth Factor Expression Via Activation of MAPK p38 and NFAT5

Purpose: We investigated the effects of cyclosporine A (CsA) on the mechanism of nerve growth factor (NGF) expression using a cultured human corneal epithelial cell line (HCECL). Methods: NGF transcription and production levels were assessed after treatment of cells with various concentrations of CsA. Activities of mitogen-activated protein kinase (MAPK), nuclear factor Kappa B (NF-kappa B), activator protein-1 (AP-1), and nuclear factor of activated T cells (NFATs) influenced by CsA were determined using a luciferase assay. The translocation activity of NFAT5 was assessed by confocal microscopy and Western immunoblotting after CsA treatment. Transcriptional activity of NGF was measured after pretreatment of cells with SB20429 (a p38 inhibitor) and NFAT5 small interfering RNA. Results: NGF was induced after treatment with CsA, but not dexamethasone, in the HCECL. NGF expression was mediated via p38 phosphorylation and NFAT5 activation. Transcriptional activities of NF-kappa B, AP-1, and NFAT1 were not stimulated by CsA; however, nuclear translocation of NFAT5 was markedly upregulated by CsA. CsA-induced NGF production was markedly decreased on inhibition of NFAT5 or SB20429. Conclusions: CsA is a potent inducer of NGF in the HCECL. These results suggest that CsA mediates NGF expression through activation of p38 and NFAT5.