Adenosine suppresses activation of nuclear factor-kappaB selectively induced by tumor necrosis factor in different cell types

Oncogene. 2003 Feb 27;22(8):1206-18. doi: 10.1038/sj.onc.1206184.

Abstract

Adenosine is an endogenous immunomodulator that has been shown to exhibit anti-inflammatory and immunosuppressive properties through a mechanism that is not fully established. Owing to the pivotal role of nuclear factor (NF)-kappaB in these responses, we tested the hypothesis that adenosine mediates its effects through suppression of NF-kappaB activation. We investigated the effects of adenosine on NF-kappaB activation induced by various inflammatory agents in human myeloid KBM-5 cells. The treatment of these cells with adenosine suppressed TNF-induced NF-kappaB activation, but had no effect on activation of another redox-sensitive transcription factor, AP-1. These effects were not restricted to myeloid cells, as NF-kappaB activation in other lymphocytic and epithelial cell types was also inhibited. The effect on TNF-induced NF-kappaB activation was selective as adenosine had minimal effect on NF-kappaB activation induced by H(2)O(2), PMA, LPS, okadaic acid, or ceramide, suggesting differences in the pathway leading to NF-kappaB activation by different agents. Adenosine also suppressed NF-kappaB-dependent reporter gene expression activated by TNF or by overexpression of TNFR1, TRAF 2, NIK, and p65 subunit of NF-kappaB. The suppression of TNF-induced NF-kappaB activation by adenosine was found not to be because of inhibition of TNF-induced IkappaBalpha phosphorylation and degradation or IkappaBalpha kinase activation. The suppression of TNF-induced NF-kappaB activation was unique to adenosine, as neither its metabolites (inosine, AMP, and ATP) nor pyrimidines (thymidine and uridine) had any effect. Overall, our results clearly demonstrate that adenosine selectively suppresses TNF-induced NF-kappaB activation, which may contribute to its role in suppression of inflammation and of the immune system.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine / pharmacology*
  • Alkaline Phosphatase / biosynthesis
  • Alkaline Phosphatase / genetics
  • Antigens, CD / physiology
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Ceramides / pharmacology
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • HeLa Cells / drug effects
  • HeLa Cells / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Kinase
  • I-kappa B Proteins / physiology
  • Jurkat Cells / drug effects
  • Jurkat Cells / metabolism
  • Kidney / cytology
  • Kidney / embryology
  • Leukemia, Myeloid / pathology
  • Lipopolysaccharides / pharmacology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology
  • Okadaic Acid / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Proteins / antagonists & inhibitors
  • Proteins / physiology
  • Purinergic P1 Receptor Agonists
  • Receptors, Purinergic P1 / physiology
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • TNF Receptor-Associated Factor 2
  • Tetradecanoylphorbol Acetate / pharmacology
  • Thymidine / pharmacology
  • Transcription, Genetic / drug effects*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Uridine / pharmacology

Substances

  • Antigens, CD
  • Ceramides
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Proteins
  • Purinergic P1 Receptor Agonists
  • Receptors, Purinergic P1
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Okadaic Acid
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • NF-kappa B kinase
  • Alkaline Phosphatase
  • Adenosine
  • Tetradecanoylphorbol Acetate
  • Thymidine
  • Uridine