title: C/EBPβ-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury.
abstract: Amplification of liver injury is mediated by macrophages but the signaling by which the macrophage inflammasome enhances liver injury is not completely understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) is a critical signaling molecule for macrophages because expression of a dominant inhibitor of C/EBPβ DNA-binding sites or a targeted deletion of C/EBPβ results in impaired macrophage differentiation. We reported that expression of the phosphorylation-mutant C/EBPβ-Glu217, which mimics phosphorylated C/EBPβ-Thr217, was sufficient to confer macrophage survival to Anthrax lethal toxin. Here, using primary hepatocytes, primary liver macrophages, dominant positive and negative transgenic mice of the C/EBPβ-Thr217 phosphoacceptor, macrophage ablation, and an inhibitory peptide of C/EBPβ-Thr217 phosphorylation, we determined that this phosphorylation is essential for the activation of the inflammasome in liver macrophages and for the hepatocyte apoptosis induced by hepatotoxins that results in liver injury. Similar findings were observed in the livers of patients with acute injury induced by Toxic Oil Syndrome.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Biomedical Sciences Program, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Buck
authors.affiliation: Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Solis-Herruzo
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.|Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Biomedical Sciences Program, University of California, San Diego, La Jolla, CA, USA.|Clinical Translational Research Institute, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Chojkier
mesh_terms: D000818:Animals; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D008264:Macrophages / Q000276:immunology*; D008822:Mice, Transgenic; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D058847:Inflammasomes