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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.
J Pharmacol Exp Ther. 2004 Dec; 311(3):1232-40.JP

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.

Authors+Show Affiliations

Anaesthesiologische Universitätsklinik, Hugstetterstrasse 55, D-79106 Freiburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15263067

Citation

Humar, Matjaz, et al. "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, vol. 311, no. 3, 2004, pp. 1232-40.
Humar M, Andriopoulos N, Pischke SE, et al. 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. J Pharmacol Exp Ther. 2004;311(3):1232-40.
Humar, M., Andriopoulos, N., Pischke, S. E., Loop, T., Schmidt, R., Hoetzel, A., Roesslein, M., Pahl, H. L., Geiger, K. K., & Pannen, B. H. (2004). 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, 311(3), 1232-40.
Humar M, et al. 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. J Pharmacol Exp Ther. 2004;311(3):1232-40. PubMed PMID: 15263067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Humar,Matjaz, AU - Andriopoulos,Nikolaos, AU - Pischke,Soeren E, AU - Loop,Torsten, AU - Schmidt,Rene, AU - Hoetzel,Alexander, AU - Roesslein,Martin, AU - Pahl,Heike L, AU - Geiger,Klaus K, AU - Pannen,Benedikt H J, Y1 - 2004/07/19/ PY - 2004/7/21/pubmed PY - 2005/1/14/medline PY - 2004/7/21/entrez SP - 1232 EP - 40 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 311 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15263067/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15263067 DB - PRIME DP - Unbound Medicine ER -