title: Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity.
abstract: Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Bollmann
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Art
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Henke
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schrick
authors.affiliation: Department of Dermatology, Johannes Gutenberg-University Medical Center, Mainz, Germany Core Facility Lentiviral Transduction Service, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Besche
authors.affiliation: Department of Dermatology, Johannes Gutenberg-University Medical Center, Mainz, Germany Core Facility Lentiviral Transduction Service, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Siuda
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Handler
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Bauer
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Behnke
authors.affiliation: pharmazentrum frankfurt/ZAFES, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Mönch
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Härdle
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.affiliation: Pharmaceutical Institute, University Tuebingen, Tuebingen, Germany.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: pharmazentrum frankfurt/ZAFES, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany kleinert@uni-mainz.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.affiliation: Department of Pharmacology, Johannes Gutenberg-University Medical Center, Mainz, Germany pautz@uni-mainz.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pautz
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D063326:Exosome Multienzyme Ribonuclease Complex / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; C105789:KHSRP protein, human; C507913:Khsrp protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D013267:Stilbenes; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D063326:Exosome Multienzyme Ribonuclease Complex; D000077185:Resveratrol