title: IκBζ is a transcriptional key regulator of CCL2/MCP-1.
abstract: CCL2, also referred to as MCP-1, is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive CCL2 secretion has been linked to many inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that IκBζ, an atypical IκB family member and transcriptional coactivator required for the selective expression of a subset of NF-κB target genes, is a key activator of the Ccl2 gene. IκBζ-deficient macrophages exhibited impaired secretion of CCL2 when challenged with diverse inflammatory stimuli, such as LPS or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IκBζ. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IκBζ is directly recruited to the proximal promoter region of the Ccl2 gene and is required for transcription-enhancing histone H3 at lysine-4 trimethylation. Finally, IκBζ-deficient mice showed significantly impaired CCL2 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IκBζ in mediating the targeted recruitment of monocytes in response to local inflammatory events.
authors.affiliation: Interfaculty Institute for Biochemistry, Eberhard Karls University, D-72076 Tübingen, Germany.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hildebrand
authors.forename: Eva
authors.initials: E
authors.lastname: Alexander
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hörber
authors.forename: Simon
authors.initials: S
authors.lastname: Lehle
authors.forename: Kerstin
authors.initials: K
authors.lastname: Obermayer
authors.forename: Niels-Arne
authors.initials: NA
authors.lastname: Münck
authors.forename: Oliver
authors.initials: O
authors.lastname: Rothfuss
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
authors.forename: Masami
authors.initials: M
authors.lastname: Morimatsu
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ehrchen
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics* / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins