beta-D-Glucoside suppresses tumor necrosis factor-induced activation of nuclear transcription factor kappaB but potentiates apoptosis

J Biol Chem. 2004 Aug 6;279(32):33768-81. doi: 10.1074/jbc.M403424200. Epub 2004 May 25.

Abstract

Mangiferin, a natural polyphenol is known to exhibit anti-inflammatory, antioxidant, and antiviral effects. However the molecular mechanism underlying these effects has not been well characterized. Because NF-kappaB plays an important role in these processes, it is possible that mangiferin modulates NF-kappaB activation. Our results show that mangiferin blocks tumor necrosis factor (TNF)-induced NF-kappaB activation and NF-kappaB-dependent genes like ICAM1 and COX2. The effect was mediated through inhibition of IKK activation and subsequent blocking of phosphorylation and degradation of IkappaBalpha. In addition, mangiferin inhibits TNF-induced p65 phosphorylation as well as translocation to the nucleus and also inhibits NF-kappaB activation induced by other inflammatory agents like PMA, ceramide, and SA-LPS. Mangiferin, similar to the other known antioxidants, NAC and PDTC, inhibits TNF-induced reactive oxygen intermediate (ROI) generation. Since intracellular glutathione (GSH) levels are known to modulate NF-kappaB levels, we measured the levels of GSH. Mangiferin enhances glutathione level by almost 2-fold more than other anti-oxidants, and at the same time it decreases the levels of GSSG and increases the activity of catalase. Depletion of GSH by buthionine sulfoximine led to a significant reversal of mangiferin effect. Hence mangiferin with its ability to inhibit NF-kappaB and increase the intracellular GSH levels may prove to be a potent drug for anti-inflammatory and antioxidant therapy. Mangiferin-mediated down-regulation of NF-kappaB also potentiates chemotherapeutic agent-mediated cell death, suggesting a role in combination therapy for cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents
  • Antineoplastic Agents / pharmacology
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms
  • Buthionine Sulfoximine / pharmacology
  • Calcium-Binding Proteins / metabolism
  • Catalase / metabolism
  • Cell Line
  • Cyclooxygenase 2
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Gene Expression / drug effects
  • Glutamate-Cysteine Ligase / genetics
  • Glutathione / analysis
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Intercellular Adhesion Molecule-1 / genetics
  • Isoenzymes / genetics
  • Jurkat Cells
  • Lymphoma, Large B-Cell, Diffuse
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Synaptotagmin I
  • Synaptotagmins
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Xanthones / pharmacology*

Substances

  • Anti-Infective Agents
  • Antineoplastic Agents
  • Antioxidants
  • Calcium-Binding Proteins
  • Isoenzymes
  • Membrane Glycoproteins
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Synaptotagmin I
  • Tumor Necrosis Factor-alpha
  • Xanthones
  • Intercellular Adhesion Molecule-1
  • Synaptotagmins
  • mangiferin
  • Buthionine Sulfoximine
  • Catalase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Glutamate-Cysteine Ligase
  • Glutathione