Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes

Natalia V. Giltiay, Alexander A. Karakashian, Alexander P. Alimov, Sandy Ligthle, Mariana N. Nikolova-Karakashian

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26 Scopus citations


Interleukin-1β (IL-1β) is a major inducer of liver acute-phase protein expression in response to infection. Several transcription factors, including CCAAT/enhancer binding protein (C/EBP), are known mediators in this process, although the mechanisms by which they modulate IL-1β's action are not completely understood. Activation of sphingomyelinase (SMase) and the subsequent generation of ceramide are early steps in the IL-1β signaling cascade. In this study, we investigate the role of ceramide in the IL-1β regulation of C/EBP in primary hepatocytes. The C/EBP DNA binding activity was found to increase in a dose-dependent manner after stimulation with IL-1β and exogenous addition of C2-ceramide or treatment with SMase. These changes were accompanied by an increase in the nuclear content of C/EBPβ. Both IL-1β and ceramide led to extracellular signal-regulated kinase 1/2 (ERK1/2) activation as early as 15 min after treatment. Furthermore, the increase of cellular ceramide content resulted in increased phosphorylation of C/EBPβ at serine 105 at later time points. Concurrently, the cytosolic levels of C/EBPβ decreased, suggesting that IL-1β and ceramide induced nuclear translocation of C/EBPβ. Ceramide-induced C/EBPβ phosphorylation, translocation, and DNA binding were suppressed by the addition of PD98059, an inhibitor of ERK1/2 phosphorylation. These results suggest that ceramide and ERK mediate a pathway in the IL-1β signaling cascade, which results in rapid posttranslational activation of C/EBPβ.

Original languageEnglish
Pages (from-to)2497-2505
Number of pages9
JournalJournal of Lipid Research
Issue number11
StatePublished - Nov 2005


  • Acute-phase protein
  • Extracellular signal-regulated kinase
  • Inflammation
  • Liver
  • Sphingomyelinase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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