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-B plays an important role in these processes, it is possible that mangiferin modulates NF-B activation. Our results show that mangiferin blocks tumor necrosis factor (TNF)-induced NF-B activation and NF-B-dependent genes like ICAM1 and COX2. The effect was mediated through inhibition of IKK activation and subsequent blocking of phosphorylation and degradation of IB␣. In addition, mangiferin inhibits TNF-induced p65 phosphorylation as well as translocation to the nucleus and also inhibits NF-B 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-B levels, we measured the levels of GSH. Mangiferin enhances glutathione level by almost 2-fold more than other antioxidants, 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-B 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-B also potentiates chemotherapeutic agent-mediated cell death, suggesting a role in combination therapy for cancer.

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Considering the role of interleukin-8 (IL-8) in a large number of acute and chronic inflammatory diseases, the regulation of IL-8-mediated biological responses is important. Alpha-melanocyte-stimulating hormone (a-MSH), a tridecapeptide, inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that a-MSH interacts predominantly with melanocortin-1 receptors and inhibits several IL-8-induced biological responses in macrophages and neutrophils. It downregulated receptors for IL-8 but not for TNF, IL-4, IL-13 or TNF-related apoptosisinducing ligand (TRAIL) in neutrophils. It down-regulated CXCR type 1 and 2 but not mRNA levels. a-MSH did not inhibit IL-8 binding in purified cell membrane or affinitypurified CXCR. IL-8 or anti-CXCR Ab protected against a-MSH-mediated inhibition of IL-8 binding. The level of neutrophil elastase, a specific serine protease, but not cathepsin G or proteinase 3 increased in a-MSH-treated cells, and restoration of CXCR by specific neutrophil elastase or serine protease inhibitors indicates the involvement of elastase in a-MSH-induced down-regulation of CXCR. These studies suggest that a-MSH inhibits IL-8-mediated biological responses by down-regulating CXCR through induction of serine protease and that a-MSH acts as a potent immunomodulator in neutrophil-driven inflammatory distress.

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