Inhibition of activator protein 1 by barbiturates is mediated by differential effects on mitogen-activated protein kinases and the small G proteins ras and rac-1. The Journal of pharmacology and experimental therapeutics. [J Pharmacol Exp Ther] Journal article

Title	Inhibition of activator protein 1 by barbiturates is mediated by differential effects on mitogen-activated protein kinases and the small G proteins ras and rac-1.
Author(s)	Humar M, Andriopoulos N, Pischke SE, Loop T, Schmidt R, Hoetzel A, Roesslein M, Pahl HL, Geiger KK, Pannen BH
Institution	Anaesthesiologische Universitätsklinik, Hugstetterstrasse 55, D-79106 Freiburg, Germany.
Source	J Pharmacol Exp Ther 2004 Dec; 311(3):1232-40.
MeSH	Antigens, CD3 Barbiturates Electrophoretic Mobility Shift Assay Genes, Reporter Humans JNK Mitogen-Activated Protein Kinases Luciferases MAP Kinase Kinase 4 Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Neuropeptides Nuclear Proteins Proto-Oncogene Proteins c-jun Proto-Oncogene Proteins p21(ras) Research Support, Non-U.S. Gov't T-Lymphocytes Transcription Factor AP-1 p38 Mitogen-Activated Protein Kinases rac GTP-Binding Proteins rac1 GTP-Binding Protein ras Proteins
Abstract	Barbiturates are known to suppress protective immunity, and their therapeutic use is associated with nosocomial infections. Although barbiturates inhibit T cell proliferation, differentiation, and cytokine synthesis, only thiobarbiturates markedly reduce the activation of immune regulatory transcription factors such as nuclear factor-kappaB and nuclear factor of activated T cells. In this study, we investigated barbiturate-mediated effects on the regulation of the transcription factor activator protein 1 (AP-1) in primary T lymphocytes. We show that both thiobarbiturates and their oxy-analogs inhibit AP-1-dependent gene expression and AP-1 complex formation at clinically relevant doses. Furthermore, mitogen-activated protein (MAP) kinase activity, which transcriptionally and posttranslationally regulates AP-1 complex formation, is suppressed by most barbiturates. CD3/CD28- or phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation or c-jun NH2-terminal kinase (JNK) 1/2 kinase activity was significantly diminished by pentobarbital, thiamylal, secobarbital, or methohexital treatment. These barbiturates also inhibited the initiators of the MAP kinase cascade, the small G proteins ras and rac-1, and prevented binding to their partners raf-1 and PAK, respectively. Thiopental, unlike the other barbiturates, only reduced ras and JNK activity upon direct CD3/CD28 receptor engagement. Contrarily, upon PMA/ionomycin stimulation, thiopental blocked AP-1-dependent gene expression independently of the small G protein ras and MAP kinases, thus suggesting an additional, unknown mechanism of AP-1 regulation. In conclusion, our results contribute to the explanation of a clinically manifested immune suppression in barbiturate-treated patients and support the idea of a MAP kinase-independent regulation of AP-1 by PKC and calcium in human T cells.
Language	eng
Pub Type(s)	Journal Article
PubMed ID	15263067

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