beta-D-Glucoside suppresses tumor necrosis factor-induced activation of nuclear transcription factor kappaB but potentiates apoptosis.
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.
Sarkar
Abira
A
Centre for DNA Fingerprinting & Diagnostics, Laboratory of Immunology, Nacharam, Hyderabad 500 076, India.
Sreenivasan
Yashin
Y
Ramesh
Govindarajan T
GT
Manna
Sunil K
SK
D000818:Animals; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044004:Xanthones / Q000494:pharmacology*
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D002135:Calcium-Binding Proteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D050863:Synaptotagmin I; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; D018799:Intercellular Adhesion Molecule-1; D050857:Synaptotagmins; C013592:mangiferin; D019328:Buthionine Sulfoximine; D002374:Catalase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione