title: Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, accounting for most cases of dementia in elderly individuals, and effective therapies are still lacking. This study was designed to investigate the anti-inflammatory properties of sulforaphane against Aβ1-42 monomers in human THP-1 microglia-like cells. The results showed that sulforaphane preferentially inhibited cathepsin B- and caspase-1-dependent NLRP3 inflammasome activation induced by mostly Aβ1-42 monomers, an effect that potently reduced excessive secretion of the proinflammatory cytokine interleukin-1β (IL-1β). Subsequent mechanistic studies revealed that sulforaphane mitigated the activation of signal transducer and activator of transcription-1 induced by Aβ1-42 monomers. Sulforaphane also increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which was followed by upregulation of heme-oxygenase 1 (HO-1). The anti-inflammatory effect of sulforaphane on Aβ1-42-induced IL-1β production was diminished by small interfering RNA-mediated knockdown of Nrf2 or HO-1. Moreover, sulforaphane significantly attenuated the levels of microRNA-146a, which is selectively upregulated in the temporal cortex and hippocampus of AD brains. The aforementioned effects of sulforaphane were replicated by the tyrosine kinase inhibitor, herbimycin A, and Nrf2 activator. These results indicate that signal transducer and activator of transcription-1 dephosphorylation, HO-1 and its upstream effector, Nrf2, play a pivotal role in triggering an anti-inflammatory signaling cascade of sulforaphane that results in decreases of IL-1β release and microRNA-146a production in Aβ1-42-stimulated human microglia-like cells. These findings suggest that the phytochemical sulforaphane has a potential application in AD therapeutics.
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Ye Won
authors.initials: YW
authors.lastname: An
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Kyoung A
authors.initials: KA
authors.lastname: Jhang
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Woo
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Korea; Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University, Seoul, Korea. Electronic address: younghae@ewha.ac.kr.
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002401:Cathepsin B / Q000378:metabolism; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013454:Sulfoxides
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010446:Peptide Fragments; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013454:Sulfoxides; C075222:amyloid beta-protein (1-42); C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D002401:Cathepsin B; C016766:sulforaphane
keywords: Alzheimer's disease; NLRP3 inflammasome; Nrf2/HO-1; STAT-1; Sulforaphane; miRNA-146a