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Originally published In Press as doi:10.1194/jlr.M700227-JLR200 on August 10, 2007

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Journal of Lipid Research, Vol. 48, 2443-2452, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation

Kristina Rutkute*, Reto H. Asmis{dagger} and Mariana N. Nikolova-Karakashian1,*

* Department of Physiology, University of Kentucky, A. B. Chandler Medical Center, Lexington, KY 40536
{dagger} Division of Nephrology, University of Texas Health Science Center at San Antonio and Audie Murphy Veterans Hospital, San Antonio, TX 78284

Published, JLR Papers in Press, August 10, 2007.

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

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-1ß (IL-1ß) 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-1ß 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-1ß, 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-1ß response. Importantly, the GSH decline, NSMase activation, and IL-1ß 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-1ß by inducing NSMase-2 activity.

Supplementary key words ceramide • calorie restriction • interleukin-1 receptor-associated kinase-1 • c-Jun N-terminal kinase • reduced glutathione

Abbreviations: AdNSMase-2, adenovirus encoding mouse NSMase-2 under doxycyclin-inducible promoter; BSO, L-buthionine-S,R-sulfoximine; IL-1ß, interleukin-1ß; IL-1RI, interleukin-1ß receptor; IL-6, interleukin-6; IRAK-1, interleukin-1 receptor-associated kinase-1; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; NAC, N-acetylcysteine; NBD-SM, 6-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino-sphingomyelin; NF-{kappa}B, nuclear factor-{kappa}B; NSMase-2, neutral sphingomyelinase-2; ROS, reactive oxygen species; TAK-1, transforming growth factor-ß-activated kinase-1; TNF-{alpha}, tumor necrosis factor-{alpha}; TRAF-6, tumor necrosis factor-associated factor-6


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