title: Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1beta in hepatocytes.
abstract: Interleukin-1beta (IL-1beta) 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-1beta's action are not completely understood. Activation of sphingomyelinase (SMase) and the subsequent generation of ceramide are early steps in the IL-1beta signaling cascade. In this study, we investigate the role of ceramide in the IL-1beta 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-1beta and exogenous addition of C2-ceramide or treatment with SMase. These changes were accompanied by an increase in the nuclear content of C/EBPbeta. Both IL-1beta 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/EBPbeta at serine 105 at later time points. Concurrently, the cytosolic levels of C/EBPbeta decreased, suggesting that IL-1beta and ceramide induced nuclear translocation of C/EBPbeta. Ceramide-induced C/EBPbeta 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-1beta signaling cascade, which results in rapid posttranslational activation of C/EBPbeta.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Giltiay
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Karakashian
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Alimov
authors.forename: Sandy
authors.initials: S
authors.lastname: Ligthle
authors.forename: Mariana N
authors.initials: MN
authors.lastname: Nikolova-Karakashian
mesh_terms: D021581:Active Transport, Cell Nucleus; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D015151:Immunoblotting; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D002518:Ceramides; D004338:Drug Combinations; D005419:Flavonoids; D007375:Interleukin-1; D007797:Laminin; C064769:N-acetylsphingosine; D009841:Oligonucleotides; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one