Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1.
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.
Biochemistry Department, University of Missouri, Columbia, Missouri, United States of America; Interdisciplinary Neuroscience Program, University of Missouri, Columbia, Missouri, United States of America; Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Grace Y
GY
Sun
Biochemistry Department, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Zihong
Z
Chen
Division of Biological Sciences, University of Missouri, Columbia, Missouri, United States of America.
Kimberly J
KJ
Jasmer
Interdisciplinary Neuroscience Program, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Dennis Y
DY
Chuang
Interdisciplinary Neuroscience Program, University of Missouri, Columbia, Missouri, United States of America; Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Zezong
Z
Gu
Biochemistry Department, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Mark
M
Hannink
Biochemistry Department, University of Missouri, Columbia, Missouri, United States of America; Center for Botanical Interaction Studies, University of Missouri, Columbia, Missouri, United States of America.
Agnes
A
Simonyi
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D011794:Quercetin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D009569:Nitric Oxide; D011794:Quercetin; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases