Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation
Oxidative stress and inflammation are fundamental for the onset of aging and appear to be causatively linked. Previously, we reported that hepatocytes from aged rats, compared with young rats, are hyperresponsive to interleukin-1β (IL-1β) stimulation and exhibit more potent c-Jun N-terminal kinase (...
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| Format: | Article |
| Language: | English |
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Elsevier
2007-11-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520424435 |
| _version_ | 1830134982581944320 |
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| author | Kristina Rutkute Reto H. Asmis Mariana N. Nikolova-Karakashian |
| author_facet | Kristina Rutkute Reto H. Asmis Mariana N. Nikolova-Karakashian |
| author_sort | Kristina Rutkute |
| collection | DOAJ |
| description | Oxidative stress and inflammation are fundamental for the onset of aging and appear to be causatively linked. Previously, we reported that hepatocytes from aged rats, compared with young rats, are hyperresponsive to interleukin-1β (IL-1β) stimulation and exhibit more potent c-Jun N-terminal kinase (JNK) activation and attenuated interleukin-1 receptor-associated kinase-1 (IRAK-1) degradation. An age-related increase in the activity of neutral sphingomyelinase-2 (NSMase-2), a plasma membrane enzyme, was found to be responsible for the IL-1β hyperresponsiveness. The results reported here show that increased NSMase activity during aging is caused by a 60–70% decrease in hepatocyte GSH levels. GSH, at concentrations typically found in hepatocytes from young animals, inhibits NSMase activity in a biphasic dose-dependent manner. Inhibition of GSH synthesis in young hepatocytes activates NSMase, causing increased JNK activation and IRAK-1 stabilization in response to IL-1β, mimicking the hyperresponsiveness typical for aged hepatocytes. Vice versa, increased GSH content in hepatocytes from aged animals by treatment with N-acetylcysteine inhibits NSMase activity and restores normal IL-1β response. Importantly, the GSH decline, NSMase activation, and IL-1β hyperresponsiveness are not observed in aged, calorie-restricted rats. In summary, this report demonstrates that depletion of cellular GSH during aging plays an important role in regulating the hepatic response to IL-1β by inducing NSMase-2 activity. |
| first_indexed | 2024-12-17T07:23:38Z |
| format | Article |
| id | doaj.art-6f35b2c24e33429cbd390460962015bb |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T07:23:38Z |
| publishDate | 2007-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-6f35b2c24e33429cbd390460962015bb2022-12-21T21:58:42ZengElsevierJournal of Lipid Research0022-22752007-11-01481124432452Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammationKristina Rutkute0Reto H. Asmis1Mariana N. Nikolova-Karakashian2Department of Physiology, University of Kentucky, A. B. Chandler Medical Center, Lexington, KY 40536Division of Nephrology, University of Texas Health Science Center at San Antonio and Audie Murphy Veterans Hospital, San Antonio, TX 78284Department of Physiology, University of Kentucky, A. B. Chandler Medical Center, Lexington, KY 40536Oxidative stress and inflammation are fundamental for the onset of aging and appear to be causatively linked. Previously, we reported that hepatocytes from aged rats, compared with young rats, are hyperresponsive to interleukin-1β (IL-1β) stimulation and exhibit more potent c-Jun N-terminal kinase (JNK) activation and attenuated interleukin-1 receptor-associated kinase-1 (IRAK-1) degradation. An age-related increase in the activity of neutral sphingomyelinase-2 (NSMase-2), a plasma membrane enzyme, was found to be responsible for the IL-1β hyperresponsiveness. The results reported here show that increased NSMase activity during aging is caused by a 60–70% decrease in hepatocyte GSH levels. GSH, at concentrations typically found in hepatocytes from young animals, inhibits NSMase activity in a biphasic dose-dependent manner. Inhibition of GSH synthesis in young hepatocytes activates NSMase, causing increased JNK activation and IRAK-1 stabilization in response to IL-1β, mimicking the hyperresponsiveness typical for aged hepatocytes. Vice versa, increased GSH content in hepatocytes from aged animals by treatment with N-acetylcysteine inhibits NSMase activity and restores normal IL-1β response. Importantly, the GSH decline, NSMase activation, and IL-1β hyperresponsiveness are not observed in aged, calorie-restricted rats. In summary, this report demonstrates that depletion of cellular GSH during aging plays an important role in regulating the hepatic response to IL-1β by inducing NSMase-2 activity.http://www.sciencedirect.com/science/article/pii/S0022227520424435ceramidecalorie restrictioninterleukin-1 receptor-associated kinase-1c-Jun N-terminal kinasereduced glutathione |
| spellingShingle | Kristina Rutkute Reto H. Asmis Mariana N. Nikolova-Karakashian Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation Journal of Lipid Research ceramide calorie restriction interleukin-1 receptor-associated kinase-1 c-Jun N-terminal kinase reduced glutathione |
| title | Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation |
| title_full | Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation |
| title_fullStr | Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation |
| title_full_unstemmed | Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation |
| title_short | Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation |
| title_sort | regulation of neutral sphingomyelinase 2 by gsh a new insight to the role of oxidative stress in aging associated inflammation |
| topic | ceramide calorie restriction interleukin-1 receptor-associated kinase-1 c-Jun N-terminal kinase reduced glutathione |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520424435 |
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