Abstract
Thalidomide ([+]-alpha-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-kappaB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-kappaB activation. We investigated the effects of thalidomide on NF-kappaB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kappaB activation, with optimum effect occurring at 50 microg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H(2)O(2)-induced NF-kappaB activation but had no effect on NF-kappaB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-kappaB (IkappaBalpha), abrogation of IkappaBalpha kinase activation, and inhibition of NF-kappaB-dependent reporter gene expression. Thalidomide abolished the NF-kappaB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kappaB-inducing kinase, but not that activated by the p65 subunit of NF-kappaB. Overall, our results clearly demonstrate that thalidomide suppresses NF-kappaB activation specifically induced by TNF and H(2)O(2) and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / physiology
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Cell Line
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Ceramides / pharmacology*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Genes, Reporter / drug effects
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Genes, Reporter / immunology
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HeLa Cells
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Humans
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Hydrogen Peroxide / antagonists & inhibitors*
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Hydrogen Peroxide / pharmacology
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I-kappa B Kinase
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I-kappa B Proteins*
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Immunosuppressive Agents / pharmacology*
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Jurkat Cells
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Kidney / cytology
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Kidney / drug effects
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Kidney / embryology
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Lipopolysaccharides / pharmacology*
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Myeloid Cells / drug effects
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Myeloid Cells / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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NF-kappaB-Inducing Kinase
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Okadaic Acid / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Proteins / antagonists & inhibitors
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Proteins / physiology
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Receptors, Tumor Necrosis Factor / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor / physiology
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Receptors, Tumor Necrosis Factor, Type I
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TNF Receptor-Associated Factor 2
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Tetradecanoylphorbol Acetate / pharmacology*
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Thalidomide / pharmacology*
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / physiology
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U937 Cells
Substances
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Antigens, CD
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Ceramides
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DNA-Binding Proteins
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Enzyme Inhibitors
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I-kappa B Proteins
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Immunosuppressive Agents
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Lipopolysaccharides
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NF-kappa B
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NFKBIA protein, human
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Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Okadaic Acid
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Thalidomide
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Hydrogen Peroxide
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Tetradecanoylphorbol Acetate