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.
Highlights
The inflammasome is a protein complex that is essential for triggering activation of inflammatory reactions in macrophages as well as the consequent macrophage activation[1,10,11]
We showed that mice expressing the dominant positive, phosphorylation mimic C/ EBPβ -Glu[217] transgene were more susceptible than control CCAAT/Enhancer Binding Protein-β (C/EBPβ) -wt mice to liver injury induced by Fas-R activation with Jo-2 Ab, judging by the serum ALT levels (P < 0.0001) (Fig. 1a) and histology (Supplementary Fig. 1)
Control cultured primary hepatocytes from C/EBPβ -wt untreated with Jo-2 had less than 5% baseline apoptosis. (c) Jo-2 Ab stimulated a greater infiltration of F4/80+ macrophage inflammatory cells in the livers of C/EBPβ -Glu[217] mice than in the livers of C/EBPβ -wt mice (P < 0.01). (d) Jo-2 Ab induced a greater area of hepatocyte apoptotic damage in the livers of C/EBPβ -Glu[217] mice than in the livers of C/EBPβ -wt mice (P < 0.005)
Summary
The inflammasome is a protein complex that is essential for triggering activation of inflammatory reactions in macrophages as well as the consequent macrophage activation[1,10,11]. C/EBPβ expression is dramatically increased during differentiation of these cells, and is induced by macrophage modulators (LPS, IL-1, G-CSF, TGFβ , vitamin D, retinoic acid)[13,17]. In this context, we and others have shown that phosphorylation of C/EBPβ by Ribosomal S-Kinase-2 (RSK-2), which is activated directly by Extracellular-Regulated Kinase (ERK)-1/2 phosphorylation, plays an essential role in the ERK/ Mitogen Activated www.nature.com/scientificreports/. We investigated whether signaling through phosphorylation of C/EBPβ -Thr[217], a potential novel therapeutic target, might be a major mechanism responsible for liver inflammation and injury through the activation of the inflammasome in liver macrophages. We studied the effects of C/EBPβ -Phospho-Thr[217] signaling that is evolutionarily conserved (identical in human C/EBPβ -Phospho-Thr266) on macrophage inflammasome activity and liver injury induced by hepatotoxins in mice and humans
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