title: The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression.
abstract: Macrophages constitute a first line of pathogen defense by triggering a number of inflammatory responses and the secretion of various pro-inflammatory cytokines. Recently, we and others found that IκBζ, an atypical IκB family member and transcriptional coactivator of selected NF-κB target genes, is essential for macrophage expression of a subset of pro-inflammatory cytokines, such as IL-6, IL-12, and CCL2. Despite defective pro-inflammatory cytokine expression, however, IκBζ-deficient mice develop symptoms of chronic inflammation. To elucidate this discrepancy, we analyzed a regulatory role of IκBζ for the expression of anti-inflammatory cytokines and identified IκBζ as an essential activator of IL-10 expression. LPS-challenged peritoneal and bone marrow-derived macrophages from IκBζ-deficient mice revealed strongly decreased transcription and secretion of IL-10 compared with wild-type mice. Moreover, ectopic expression of IκBζ was sufficient to stimulate Il10 transcription. On the molecular level, IκBζ directly activated the Il10 promoter at a proximal κB site and was required for the transcription-enhancing trimethylation of histone 3 at lysine 4. Together, our findings show for the first time the IκBζ-dependent expression of an anti-inflammatory cytokine that is crucial in controlling immune responses.
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hörber
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hildebrand
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and.
authors.forename: Wolfgang S
authors.initials: WS
authors.lastname: Lieb
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lorscheid
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and.
authors.forename: Stephan
authors.initials: S
authors.lastname: Hailfinger
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and; the German Cancer Consortium (DKTK) and German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: kso@uni-tuebingen.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: From the Interfaculty Institute of Biochemistry, Department of Molecular Medicine, University of Tübingen, 72076 Tübingen, Germany and. Electronic address: frank.essmann@uni-tuebingen.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018836:Inflammation Mediators; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D016753:Interleukin-10
keywords: NF-κB; NF-κB transcription factor; immunosuppressor; interleukin; macrophage