Thalidomide Suppresses NF-kappa B Activation Induced by TNF and H2O2, but Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester

J Immunol. 2002 Mar 15;168(6):2644-51. doi: 10.4049/jimmunol.168.6.2644.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / physiology
  • Cell Line
  • Ceramides / pharmacology*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Genes, Reporter / drug effects
  • Genes, Reporter / immunology
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / antagonists & inhibitors*
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Kinase
  • I-kappa B Proteins*
  • Immunosuppressive Agents / pharmacology*
  • Jurkat Cells
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / embryology
  • Lipopolysaccharides / pharmacology*
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Okadaic Acid / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Proteins / antagonists & inhibitors
  • Proteins / physiology
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Thalidomide / pharmacology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / physiology
  • U937 Cells

Substances

  • Antigens, CD
  • Ceramides
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Okadaic Acid
  • Thalidomide
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • NF-kappa B kinase
  • Tetradecanoylphorbol Acetate