| Upregulated innate immune response is a hallmark of the aging process, and its sustained activation is known to contribute to a variety of agingassociated diseases. Thus, elucidation of the mechanisms underlying the age-related changes in the innate immunity may help to understand the fundamental mechanisms of aging.; Interleukin-1beta (IL-1beta) is a major mediator of the innate immune response, and c-Jun N-terminal kinase (JNK) is an important component in the signaling pathway of this cytokine. This study demonstrated that hepatocytes from aged (20 month old) rats, as compared to hepatocytes from young (3 month old) rats, were hyperresponsive to stimulation by IL-1beta and exhibited more potent JNK activation. Notably, the hyperresponsiveness was not due to increased basal levels of JNK or other key components of the IL-1beta signaling pathway.; Age-related hyperresponsiveness to IL-1beta was paralleled by delayed interleukin-associated kinase-1 (IRAK-1) degradation, a terminating event in IL-1beta signaling. It was further found that the attenuation of IRAK-1 degradation was caused by an age-related increase in the activity of neutral sphingomyelinase (NSMase), a signaling enzyme activated by extrinsic stress stimuli. Neutral sphingomyelinase-2 (nSMase2), a plasma membrane-localized NSMase, was the NSMase activated by aging and was shown to participate in the induction of the hype rresponsiveness to IL-1 P. Further investigation revealed that elevation of basal nSMase2 activity resulted from age-related depletion of glutathione (GSH), which is a potent inhibitor of nSMase2 activity both in situ and in vitro. Notably, inhibition of GSH synthesis in hepatocytes from young animals was sufficient to activate NSMase, stabilize IRAK-1 and potentiate JNK activation, thus leading to hyperresponsiveness. In contrast, restoration of GSH content in hepatocytes from aged animals by antioxidant supplementation or life-long calorie restriction decreased NSMase activity and rescued normal IL-1beta responsiveness. Finally, age-related upregulation of JNK activation by IL-1beta resulted in increased production of insulin-like growth factor binding protein-1 (IGFBP-1).; In summary, this study provides evidence that age-related changes in intracellular proinflammatory signaling may arise from due to depletion of cellular antioxidant GSH, thus linking causally the onset of age-related oxidative stress and increased inflammatory response through nSMase2.; Keywords. Aging, Cytokines, Glutathione, Oxidative stress, Sphingomyelinase... |
