Differential effect of thalidomide and dexamethasone on the transcription factor NF-κ B

Tom L. Rowland, Simon M. McHugh, John Deighton, Pamela W. Ewan, Rebecca J. Dearman, Ian Kimber

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Thalidomide was initially used as a sedative during pregnancy but was withdrawn from the market due to its teratogenic effects. In vitro studies have shown that thalidomide inhibits tumour necrosis factor α (TNF-α) mRNA expression and protein production by mitogen-stimulated macrophages and activated T cells. Even at the highest concentration (10-1 mM) tested, however, TNF-α 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-κB 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-κB-mediated effects on TNF-α 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-α production. Cells were harvested at varying time points and nuclear extracts prepared. Nuclear levels of NF-κB were measured using electrophoretic mobility shift assays (EMSA) with a radiolabelled DNA probe specific for NF-κB. Results were analysed using optical densitometry. Nuclear levels of NF-κB were found to be unaffected by thalidomide at all concentrations tested, including concentrations (10-1-10-3 mM) that exhibited significant inhibition of TNF-α protein and mRNA expression. In concurrent experiments, dexamethasone was found to reduce NF-κB expression in a dose-dependent manner with maximal inhibition at the highest dose tested (10-1 mM). TNF-α 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 not act directly on NF-κB and therefore inhibits TNF-α production through another independent mechanism. © 2001 Elsevier Science B.V.
    Original languageEnglish
    Pages (from-to)49-61
    Number of pages12
    JournalInternational immunopharmacology
    Volume1
    Issue number1
    DOIs
    Publication statusPublished - 2001

    Keywords

    • Dexamethasone
    • Immunomodulation
    • NF-κB
    • Thalidomide

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