Submitted on May 15, 2007
Revised on August 9, 2007
Accepted on August 9, 2007
Regulation of neutral sphingomyelinase-2 by GSH: A new insight to the role of oxidative stress in aging-associated inflammation
Kristina Rutkute, Reto H.R. Asmis, and Mariana N. Nikolova-Karakashian
Physiology, University of Kentucky, Lexington, KY 40502
Corresponding Author: 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, as compared to young ones, are hyperresponsive to interleukin-1
(IL-1b) stimulation and exhibit more potent c-jun N-terminal kinase (JNK) activation, and attenuated interleukin 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-1 hyperresponsiveness. The results reported herein show that elevation of NSMase activity during aging is caused by a 60-70% drop in the 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-1, mimicking the hyperresponsiveness typical for aged hepatocytes. Vice versa, elevation of GSH content in hepatocytes from aged animals by treatment with N-acetylcysteine (NAC) inhibits NSMase activity and restores normal IL-1 response. Importantly, the GSH decline, NSMase activation, and IL-1 hyperresponsiveness are not observed in aged, calorie restricted rats. In summary, this manuscript demonstrates that depletion of cellular GSH during aging plays an important role in regulating the hepatic response to IL-1 by inducing NSMase-2 activity.
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