title: Regiospecific methylation of a dietary flavonoid scaffold selectively enhances IL-1β production following Toll-like receptor 2 stimulation in THP-1 monocytes.
abstract: It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4'-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.
authors.affiliation: From the Centre for Immunology and Infection, Hull York Medical School and Department of Biology and.
authors.forename: Eng-Kiat
authors.initials: EK
authors.lastname: Lim
authors.affiliation: From the Centre for Immunology and Infection, Hull York Medical School and Department of Biology and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mitchell
authors.affiliation: From the Centre for Immunology and Infection, Hull York Medical School and Department of Biology and.
authors.forename: Najmeeyah
authors.initials: N
authors.lastname: Brown
authors.affiliation: the Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Drummond
authors.affiliation: the Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: From the Centre for Immunology and Infection, Hull York Medical School and Department of Biology and. Electronic address: paul.kaye@york.ac.uk.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kaye
authors.affiliation: Department of Biology, University of York, York YO10 5DD, United Kingdom and. Electronic address: dianna.bowles@york.ac.uk.
authors.forename: Dianna J
authors.initials: DJ
authors.lastname: Bowles
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D005419:Flavonoids; D053583:Interleukin-1beta; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; C459210:quercetin 3-O-methyl ether; D003513:Cycloheximide; D011794:Quercetin; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1
keywords: IL-1β; Interleukin; Methylated Flavonols; Natural Products; Plant Natural Products; Signaling; Small Molecules; TLR Signaling; Toll-like Receptors (TLR)