Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.

Abstract

Both thalidomide and dexamethasone have been shown to inhibit the production of tumour necrosis factor alpha (TNF-alpha), but little is known of their cellular selectivity. Inhibition of monocyte TNF-alpha expression has been implicated in the clinical efficacy of thalidomide, and it has been suggested that the drug modulates only monocyte-derived cytokines. Given the importance of T lymphocyte responses in immunological disorders in which treatment with thalidomide has been successful, it is pertinent to study the effects of this drug on T cell-derived TNF-alpha. In the present investigations we have examined the influence of both thalidomide and dexamethasone on mitogen-induced elaboration of TNF-alpha by CD3+ peripheral blood mononuclear cells (PBMC) and the T cell line MOLT-4. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide or dexamethasone, and supernatants assayed for TNF-alpha and interleukin 2 (IL-2). Concurrently, PHA-stimulated PBMC were treated with 1 x 10(-1) mM thalidomide or dexamethasone and the cells fixed, permeabilised, stained with anti-CD3 and anti-TNF-alpha fluorescently labelled antibodies and analysed by flow cytometry. MOLT-4 cells were cultured in the presence or absence of the drugs following activation with phorbol myristate acetate (PMA)/ionophore, and supernatants analysed by enzyme-linked immunosorbent assay (ELISA) for cytokine expression. Thalidomide was found to inhibit PBMC-derived TNF-alpha, but not IL-2. In contrast, dexamethasone down-regulated both TNF-alpha and IL-2 in a dose-dependent manner. Thalidomide and dexamethasone both suppressed intracellular levels of TNF-alpha in CD3+ PBMC, reducing percentages of double positive staining cells by 28 and 52%, respectively, compared with controls. In addition, TNF-alpha production by CD3- PBMC was inhibited by 31% by thalidomide and by 47% by dexamethasone. In order to determine whether thalidomide was acting directly on T cells, or indirectly through effects on accessory cells, TNF-alpha production in the T cell line MOLT-4 was investigated. TNF-alpha secretion by PMA/ionophore activated MOLT-4 cells was reduced by 80% following thalidomide treatment and close to background levels following dexamethasone treatment. To verify that thalidomide was acting selectively to down-regulate TNF-alpha, IL-2 production by MOLT-4 cells was also measured and found to be unaffected by the drug. In contrast, dexamethasone reduced MOLT-4-derived IL-2 levels by 20%. These observations suggest that thalidomide, in addition to its known inhibitory effect on monocyte-derived TNF-alpha, is capable also of down-regulating T cell-derived TNF-alpha in a direct and selective manner. In addition, the inhibition of intracellular levels of TNF-alpha strengthens the evidence that the inhibitory effect of thalidomide is at the level of transcription and/or translation and does not reduce cellular TNF-alpha secretion. Such effects could explain the efficacy of thalidomide treatment in various immunological disorders where T cell activation plays an important role in the pathogenesis of the disease.

Statistics

0200400'03'05'07'09'11'13'15'17
Citations per Year

266 Citations

Semantic Scholar estimates that this publication has 266 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Rowland1999SelectiveDO, title={Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.}, author={T L Rowland and Simon M. McHugh and John Deighton and Pamela W Ewan and R . J . Dearman and Ian R Kimber}, journal={Immunology letters}, year={1999}, volume={68 2-3}, pages={325-32} }