Cyclosporin A regulates the levels of cyclophilin A in neuroblastoma cellsin culture

Cyclophilin A (CyP-A), a member of a highly conserved family of proteins, i mmunophilins, is the major intracellular receptor for the immunosuppressive drug, cyclosporin A (CsA). CyP-A is widely expressed in many tissues, but is found in the highest concentration in brain tissues and may perform crit ical neuronal functions. CsA is a known neurotoxin. Therefore, understandin g the regulation of CyP-A levels in nerve cells, particularly by CsA, is im portant. We have utilized murine neuroblastoma (NB) cells as an experimenta l model to investigate this issue. Our results show that CsA alone was suff icient to induce morphological differentiation in undifferentiated NE cells and to increase CyP-A levels as determined by immunostaining. However, ind ucing terminal differentiation by elevating adenosine 3',5'-cyclic monophos phate (cAMP) levels using either 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidi none (RO20-1724), an inhibitor of cyclic nucleotide phosphodiesterase, or p rostaglandin E-1 (PGE(1)), a stimulator of adenylate cyclase, was not suffi cient to increase CyP-A levels. CsA was required to increase CyP-A levels i n both RO20-1724- and PGE(1)-induced differentiated NB cells. Increases in CyP-A levels, however, occurred without any change in the expression of the CyP-A gene as determined by reverse-transcriptase polymerase-chain reactio n analysis using (CyP-A)-specific primers. These results suggest that CsA r egulates the level of its own binding protein, CyP-A, in both undifferentia ted and cAMP-induced differentiated NE cells in culture. (C) 1999 Elsevier Science Ltd. All rights reserved.