Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-dependent HO-1 pathway.
Abnormal nitrosative stress-induced neuroinflammation is implicated in the pathogenesis of neurodegenerative diseases. Therefore, it has been thought that nitric oxide (NO) production is a good therapeutic target. In this sense, quercetin is a good chemopreventive component, because it has free radical-scavenging and anti-inflammatory activities. However, explicit mechanisms are not clear in the lipopolysaccharide (LPS)-stimulated BV2 microglial cell line. Here, we found that quercetin significantly suppressed LPS-induced NO production and inducible NO synthase (iNOS) expression. Notably, quercetin inhibited nuclear factor-κB (NF-κB) activation by inhibiting degradation of the inhibitor of kappa Bα (IκBα) in LPS-stimulated BV2 microglial cells corresponding to the inhibitory effect of specific NF-κB inhibitors, namely proteasome inhibitor I (PSI) and MG132. Quercetin caused significant increases in the levels of heme oxgenase-1 (HO-1) mRNA and protein. Notably, treatment with an HO-1 inducer, cobalt protoporphyrin (CoPP), significantly diminished LPS-stimulated NO production. Additionally, quercetin induced the specific DNA-binding activity of nuclear factor-2-erythroid 2-related factor 2 (Nrf2), and siRNA-mediated knockdown of Nrf2 expression reduced the inhibitory effect of quercetin on LPS-stimulated NO production by inhibiting HO-1 expression, indicating that quercetin regulated NO production by inducing Nrf2-mediated HO-1 expression. Therefore, quercetin has the potential to decrease nitrosative stress by suppressing NF-κB activation and inducing Nrf2-mediated HO-1 expression.
Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.
Chang-Hee
CH
Kang
Yung Hyun
YH
Choi
Sung-Kwon
SK
Moon
Wun-Jae
WJ
Kim
Gi-Young
GY
Kim
D000818:Animals; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D011794:Quercetin / Q000494:pharmacology*
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D009569:Nitric Oxide; D011794:Quercetin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
Heme oxgenase-1; Nitric oxide; Nitric oxide synthase; Nuclear factor-2-erythroid 2-related factor 2; Nuclear factor-κB; Quercetin