title: Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages.
abstract: GILZ (glucocorticoid-induced leucine zipper) is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-κB and mitogen-activated protein kinase activation but does not seem to be involved in the severe side effects observed after glucocorticoid treatment. Therefore, GILZ might be a promising target for new therapeutic approaches. The present work focuses on the natural product curcumin, which has previously been reported to inhibit NF-κB. GILZ was inducible by curcumin in macrophage cell lines, primary human monocyte-derived macrophages, and murine bone marrow-derived macrophages. The up-regulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction or mRNA or protein stabilization but was a result of enhanced translation. Because the GILZ 3'-UTR contains AU-rich elements (AREs), we analyzed the role of the mRNA-binding protein HuR, which has been shown to promote the translation of ARE-containing mRNAs. Our results suggest that curcumin treatment induces HuR expression. An RNA immunoprecipitation assay confirmed that HuR can bind GILZ mRNA. In accordance, HuR overexpression led to increased GILZ protein levels but had no effect on GILZ mRNA expression. Our data employing siRNA in LPS-activated RAW264.7 macrophages show that curcumin facilitates its anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated bone marrow-derived macrophages from wild-type and GILZ knock-out mice demonstrated that curcumin inhibits the activity of inflammatory regulators, such as NF-κB or ERK, and subsequent TNF-α production via GILZ. In summary, our data indicate that HuR-dependent GILZ induction contributes to the anti-inflammatory properties of curcumin.
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hachenthal
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Jenny Vanessa
authors.initials: JV
authors.lastname: Valbuena-Perez
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lampe
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Astanina
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kunze
authors.affiliation: Department of Medicine, Section of Pharmacology, University of Perugia, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.affiliation: Department of Medicine, Section of Pharmacology, University of Perugia, 06132 Perugia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Diesel
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany, pharm.bio.kiemer@mx.uni-saarland.de.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D000818:Animals; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010936:Plant Extracts / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology
chemical_list: C498608:Dsip1 protein, mouse; D000067780:ELAV-Like Protein 1; D016328:NF-kappa B; D010936:Plant Extracts; D014157:Transcription Factors; D003474:Curcumin
keywords: ELAV-like protein 1 (HuR (human antigen R)); NF-κ B (NF-KB); RNA-binding protein; inflammation; innate immunity; lipopolysaccharide (LPS); mitogen-activated protein kinase (MAPK); natural product; nitric oxide