Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2005-11-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520328881 |
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| author | Natalia V. Giltiay Alexander A. Karakashian Alexander P. Alimov Sandy Ligthle Mariana N. Nikolova-Karakashian |
| author_facet | Natalia V. Giltiay Alexander A. Karakashian Alexander P. Alimov Sandy Ligthle Mariana N. Nikolova-Karakashian |
| author_sort | Natalia V. Giltiay |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T19:07:37Z |
| format | Article |
| id | doaj.art-a742162ce9d84a8fa7604f4f592d24e5 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T19:07:37Z |
| publishDate | 2005-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-a742162ce9d84a8fa7604f4f592d24e52022-12-21T21:35:57ZengElsevierJournal of Lipid Research0022-22752005-11-01461124972505Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytesNatalia V. Giltiay0Alexander A. Karakashian1Alexander P. Alimov2Sandy Ligthle3Mariana N. Nikolova-Karakashian4Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536To whom correspondence should be addressed.; Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536Interleukin-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.http://www.sciencedirect.com/science/article/pii/S0022227520328881inflammationsphingomyelinaseliveracute-phase proteinextracellular signal-regulated kinase |
| spellingShingle | Natalia V. Giltiay Alexander A. Karakashian Alexander P. Alimov Sandy Ligthle Mariana N. Nikolova-Karakashian Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes Journal of Lipid Research inflammation sphingomyelinase liver acute-phase protein extracellular signal-regulated kinase |
| title | Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes |
| title_full | Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes |
| title_fullStr | Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes |
| title_full_unstemmed | Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes |
| title_short | Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes |
| title_sort | ceramide and erk dependent pathway for the activation of ccaat enhancer binding protein by interleukin 1β in hepatocytes |
| topic | inflammation sphingomyelinase liver acute-phase protein extracellular signal-regulated kinase |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520328881 |
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