β-d-Glucoside Suppresses Tumor Necrosis Factor-induced Activation of Nuclear Transcription Factor κB but Potentiates Apoptosis

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.