Abstract
A large group of flavonoids found in fruits and vegetables have been suggested to elicit health benefits due mainly to their anti-oxidative and anti-inflammatory properties. Recent studies with immune cells have demonstrated inhibition of these inflammatory responses through down-regulation of the pro-inflammatory pathway involving NF-κB and up-regulation of the anti-oxidative pathway involving Nrf2. In the present study, the murine BV-2 microglial cells were used to compare anti-inflammatory activity of quercetin and cyanidin, two flavonoids differing by their alpha, beta keto carbonyl group. Quercetin was 10 folds more potent than cyanidin in inhibition of lipopolysaccharide (LPS)-induced NO production as well as stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression. In addition, quercetin demonstrated enhanced ability to stimulate HO-1 protein expression when cells were treated with LPS. In an attempt to unveil mechanism(s) for quercetin to enhance Nrf2/HO-1 activity under endotoxic stress, results pointed to an increase in phospho-p38MAPK expression upon addition of quercetin to LPS. In addition, pharmacological inhibitors for phospho-p38MAPK and MEK1/2 for ERK1/2 further showed that these MAPKs target different sites of the Nrf2 pathway that regulates HO-1 expression. However, inhibition of LPS-induced NO by quercetin was not fully reversed by TinPPIX, a specific inhibitor for HO-1 activity. Taken together, results suggest an important role of quercetin to regulate inflammatory responses in microglial cells and its ability to upregulate HO-1 against endotoxic stress through involvement of MAPKs.
Highlights
Recent studies have demonstrated ability for a number of botanical polyphenols to suppress oxidative stress and inflammatory responses in immune cells [1,2,3,4,5]
We investigated the ability for quercetin and cyanidin, a structurally similar flavonoid, to inhibit LPS-induced nitric oxide (NO) and to stimulate the Nrf2 pathway that leads to increased heme oxygenase 1 (HO-1) expression in BV-2 microglial cells
To better define experimental conditions that would allow us to examine the ability of quercetin and cyanidin to modulate expression of Nrf2 and HO-1 in LPS-stimulated cells, we first characterized the ability of LPS to stimulate the Nrf2/HO-1 pathway in BV-2 microglial cells
Summary
Recent studies have demonstrated ability for a number of botanical polyphenols to suppress oxidative stress and inflammatory responses in immune cells [1,2,3,4,5]. Studies on nitrosative/oxidative stress and inflammatory responses in neurodegenerative diseases have indicated the importance of the anti-oxidant pathway involving the Kelchlike ECH-associated protein 1 (Keap1)/Nuclear Factor Erythroid 2-Like 2 (NFE2L2, Nrf). Studies on nitrosative/oxidative stress and inflammatory responses in neurodegenerative diseases have indicated the importance of the anti-oxidant pathway involving the Kelchlike ECH-associated protein 1 (Keap1)/Nuclear Factor Erythroid 2-Like 2 (NFE2L2, Nrf2) This pathway is responsible for transcriptional activation of a large number of genes that are regulated by Anti-oxidant Response Elements (AREs) in their promoters. Special attention has been drawn to the beneficial aspects of Nrf2-mediated induction of heme oxygenase 1 (HO-1), the enzyme that degrades heme to generate CO, biliverdin and free iron [14] These studies have demonstrated an important role for HO-1 in immunoregulation, oxidative stress, and resistance to bacterial infection [14,15,16,17]
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