Unknown,Transcriptomics,Genomics,Proteomics

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Inhibitor of NFκB ζ (IκBζ) is a transcriptional key regulator of monocyte chemoattractant protein-1 (MCP-1/CCL2)


ABSTRACT: Monocyte chemoattractant protein 1 (MCP-1/CCL2) is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive MCP-1 secretion has been linked to many (auto)inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that the atypical inhibitor of NF-κB ζ (IκBζ), a transcriptional co-activator 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 MCP-1 when challenged with diverse inflammatory stimuli, such as lipopolysaccharide 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 required for histone H3K9 trimethylation. Finally, IκBζ-deficient mice showed significantly impaired MCP-1 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. Peritoneal macrophages from Wildtype and IκBζ-Knockout mice were either stimulated with 1µg/ml LPS for 4h or left untreated (triplicates each)

ORGANISM(S): Mus musculus

SUBMITTER: Niels-Arne Münck 

PROVIDER: E-GEOD-43075 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 macr  ...[more]

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