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Originally published In Press as doi:10.1194/jlr.M500337-JLR200 on August 16, 2005

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Journal of Lipid Research, Vol. 46, 2497-2505, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

Natalia V. Giltiay1, Alexander A. Karakashian1, Alexander P. Alimov1, Sandy Ligthle and Mariana N. Nikolova-Karakashian2

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536

Published, JLR Papers in Press, August 16, 2005. DOI 10.1194/jlr.M500337-JLR200

1 N. V. Giltiay, A. A. Karakashian, and A. P. Alimov contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: mnikolo{at}uky.edu

Interleukin-1ß (IL-1ß) 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-1ß's action are not completely understood. Activation of sphingomyelinase (SMase) and the subsequent generation of ceramide are early steps in the IL-1ß signaling cascade. In this study, we investigate the role of ceramide in the IL-1ß 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-1ß and exogenous addition of C2-ceramide or treatment with SMase. These changes were accompanied by an increase in the nuclear content of C/EBPß. Both IL-1ß 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/EBPß at serine 105 at later time points. Concurrently, the cytosolic levels of C/EBPß decreased, suggesting that IL-1ß and ceramide induced nuclear translocation of C/EBPß. Ceramide-induced C/EBPß 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-1ß signaling cascade, which results in rapid posttranslational activation of C/EBPß.

Abbreviations: AGP, {alpha}1-acid glycoprotein; AP-1, Activator Protein-1; APP, acute-phase protein; APR, acute-phase response; APRE, acute-phase response element; C/EBP, CCAAT/enhancer binding protein; ERK, extracellular signal-regulated kinase; IL-1ß, interleukin-1ß; JNK, c-Jun NH2-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NF{kappa}B, nuclear factor {kappa}B; nSMase, neutral sphingomyelinase; SerX, serine X; SM, sphingomyelin; SMase, sphingomyelinase

Supplementary key words inflammation • sphingomyelinase • liver • acute-phase protein • extracellular signal-regulated kinase


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