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Titolo:
Differential effect of thalidomide and dexamethasone on the transcription factor NF-kappa B
Autore:
Rowland, TL; McHugh, SM; Deighton, J; Ewan, PW; Dearman, RJ; Kimber, I;
Indirizzi:
Addenbrookes Hosp, Clin Res Unit, Addenbrookes Ctr Clin Invest, Cambridge CB2 2GG, England Addenbrookes Hosp Cambridge England CB2 2GG , Cambridge CB2 2GG, England Glaxo Wellcome Stevenage, Stevenage SG1 2NY, Herts, England Glaxo WellcomeStevenage Stevenage Herts England SG1 2NY , Herts, England Univ Cambridge, Addenbrookes Hosp, Dept Med, Sch Clin, Cambridge CB2 2QQ, England Univ Cambridge Cambridge England CB2 2QQ lin, Cambridge CB2 2QQ, England AstraZeneca Cent Toxicol Lab, Macclesfield SK10 4TJ, Cheshire, England AstraZeneca Cent Toxicol Lab Macclesfield Cheshire England SK10 4TJ gland
Titolo Testata:
INTERNATIONAL IMMUNOPHARMACOLOGY
fascicolo: 1, volume: 1, anno: 2001,
pagine: 49 - 61
SICI:
1567-5769(200101)1:1<49:DEOTAD>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
NECROSIS-FACTOR-ALPHA; POTENT INHIBITORS; TNF-ALPHA; ANALOGS; IMMUNOSUPPRESSION; PHOSPHODIESTERASE; GLUCOCORTICOIDS; REPLICATION; ACTIVATION; PROGRAM;
Keywords:
thalidomide; dexamethasone; immunomodulation; NF-kappa B;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
23
Recensione:
Indirizzi per estratti:
Indirizzo: McHugh, SM Addenbrookes Hosp, Clin Res Unit, Addenbrookes Ctr Clin Invest,Cambridge CB2 2GG, England Addenbrookes Hosp Cambridge England CB2 2GG CB2 2GG, England
Citazione:
T.L. Rowland et al., "Differential effect of thalidomide and dexamethasone on the transcription factor NF-kappa B", INT IMMUNO, 1(1), 2001, pp. 49-61

Abstract

Thalidomide was initially used as a sedative during pregnancy but was withdrawn from the market due to its teratogenic effects. In vitro studies haveshown that thalidomide inhibits tumour necrosis factor alpha (TNF-alpha) mRNA expression and protein production by mitogen-stimulated macrophages andactivated T cells. Even at the highest concentration (10(-1) mM) tested, however, TNF-alpha levels are inhibited only partially and the mechanism of action is unknown. In the present investigations, we have examined the influence of thalidomide on nuclear levels of NF-kappaB in human peripheral blood mononuclear cells (PBMC) following activation with mitogen or phorbol myristate acetate (PMA)/ionophore. Dexamethasone was used as a positive control due to its well-characterised mechanism of action and NF-kappaB-mediatedeffects on TNF-alpha expression. PBMC from healthy human volunteers were stimulated optimally with phytohemagglutinin (PHA) or PMA/ionophore in the presence of 10(-1)-10(-5) mM thalidomide or dexamethasone, concentrations that displayed a range of inhibitory effects on TNF-alpha production. Cells were harvested at varying time points and nuclear extracts prepared. Nuclearlevels of NF-kappaB were measured using electrophoretic mobility shift assays (EMSA) with a radiolabelled DNA probe specific for NF-kappaB. Results were analysed using optical densitometry. Nuclear levels of NF-kappaB were found to be unaffected by thalidomide at all concentrations tested, including concentrations (10(-1)-10(-3) mM) that exhibited significant inhibition of TNF-alpha protein and mRNA expression. In concurrent experiments, dexamethasone was found to reduce NF-kappaB expression in a dose-dependent manner with maximal inhibition at the highest dose tested (10(-1) mM). TNF-alpha gene expression is controlled by at least three separate transcription factors that are involved in binding to the promoter region. These observations suggest that thalidomide does nut act directly on NF-KB and therefore inhibits TNF-alpha production through another independent mechanism. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 12:28:45