title: The anti-inflammatory effects of E-α-(p-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone are mediated via HO-1 induction.
abstract: Inflammation plays a central role in the pathophysiology of many diseases. The inducible enzyme heme oxygenase-1 (HO-1) protects cells against inflammation and can be induced by electrophilic compounds like the chalcones (1,3-diphenylprop-2-enones) from the class of α,β-unsaturated carbonyl compounds. We hypothesized that the synthetic chalcone E-α-(p-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone (E-α-p-OMe-C6H4-TMC) exerts anti-inflammatory effects in RAW264.7, Jurkat lymphocytes and HK-2 cells via HO-1 induction. RAW264.7 cells were treated with lipopolysaccharide prior to E-α-p-OMe-C6H4-TMC treatment. Subsequently, HO-1 protein induction and activity were analyzed, as well as expression of pro- and anti-inflammatory mediators, transcription factors and mitogen-activated protein kinases to evaluate the possible molecular mechanism. These results were confirmed in human cell lines (Jurkat T-lymphocytes and HK-2 epithelial cells). We found that the E-α-p-OMe-C6H4-TMC exerts significant anti-inflammatory effects in a dose dependent manner, showing no toxic effects in LPS-treated RAW264.7 macrophages. E-α-p-OMe-C6H4-TMC induced HO-1 and SOD-1 protein expression and HO-1 enzyme activity, reduced the upregulation of COX-2 and iNOS, while inducing the translocation of Nrf2. NF-κB activity was attenuated following E-α-p-OMe-C6H4-TMC treatment accompanied by the downregulation of proinflammatory cytokines IL-1β, IL-6 and MCP-1. Pretreatment with E-α-p-OMe-C6H4-TMC revealed significant changes in phosphorylation of ERK and p38, but not JNK. These anti-inflammatory effects of E-α-p-OMe-C6H4-TMC were approved in Jurkat and HK-2 cells, furthermore revealing a downregulation of IL-8 and IL-10. In conclusion, it is tempting to speculate about E-α-p-OMe-C6H4-TMC as a new and non-toxic agent, inducing HO-1 in cells. This opens up new opportunities regarding the development of therapeutic agents using beneficial effects of HO-1 and its products.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Germany.
authors.forename: Kai B
authors.initials: KB
authors.lastname: Kaufmann
authors.affiliation: Department of Radiation Oncology, University Medical Center Freiburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Gothwal
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Schallner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Ulbrich
authors.affiliation: Institute of Organic Chemistry, University of Regensburg, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Rücker
authors.affiliation: Institute of Organic Chemistry, University of Regensburg, Germany. Electronic address: sabine.amslinger@chemie.uni-regensburg.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Amslinger
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Germany. Electronic address: ulrich.goebel@uniklinik-freiburg.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Goebel
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D047188:Chalcones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000608611:alpha-(4-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D000072105:Superoxide Dismutase-1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Chalcone; HO-1; Inflammation; MAPK; NF-κB; Nrf2