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Barbiturates Directly Inhibit the Calmodulin/Calcineurin Complex: a Novel Mechanism of Inhibition of Nuclear Factor of Activated T Cells

Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg Freiburg, Germany (S.E.P., T.L., A.H., R.S., H.L.P., K.K.G., B.H.J.P.), and Institute of Pharmaceutical Biology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany (C.K.)

Barbiturates are frequently used for the treatment of intracranial hypertension after brain injury but their application is associated with a profound increase in the infection rate. The mechanism of barbiturate-induced failure of protective immunity is still unknown. We provide evidence that nuclear factor of activated T cells (NFAT), an essential transcription factor in T cell activation, is a target of barbiturate-mediated immunosuppression in human T lymphocytes. Treatment of primary CD3⁺ lymphocytes with barbiturates inhibited the PMA and ionomycin induced increase in DNA binding of NFAT, whereas the activity of other transcription factors, such as Oct-1, SP-1, or the cAMP response element-binding protein, remained unaffected. Moreover, barbiturates suppressed the expression of a luciferase reporter gene under control of NFAT (stably transfected Jurkat T cells), and of the cytokine genes interleukin-2 and interferon- that contain functional binding motifs for NFAT within their regulatory promotor domains (human peripheral blood CD3⁺ lymphocytes). Neither GABA receptor-initiated signaling nor direct interactions of barbiturates with nuclear proteins affected the activity of NFAT. In contrast, barbiturates suppressed the calcineurin-dependent dephosphorylation of NFAT in intact T cells and also inhibited the enzymatic activity of calcineurin in a cell-free system, excluding upstream regulation. Thus, our results demonstrate a novel mechanism of direct inhibition of the calcineurin/calmodulin complex that may explain some of the known immunosuppressive effects associated with barbiturate treatment.

Address correspondence to: Dr. Benedikt H. J. Pannen, Anaesthesiologische Universitätsklinik, Hugstetterstrasse 55, D-79106 Freiburg, Germany. E-mail: pannen{at}nz.ukl.uni-freiburg.de

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