Serum IL-1β levels in health and disease: a population-based study. ‘The InCHIANTI study’

Iorio, Angelo Di; Ferrucci, Luigi; Sparvieri, Eleonora; Cherubini, Antonio; Volpato, Stefano; Corsi, Annamaria; Bonafè, M.; Franceschi, Claudio; Abate, G; Paganelli, Roberto

doi:10.1016/s1043-4666(03)00152-2

Cited by 98 publications

(62 citation statements)

References 27 publications

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“…However, despite the fact that basal levels of some cytokines, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), seem to increase with age, these increases are modest, and it is not yet clear whether they are sufficient to evoke an inflammatory response. Moreover, the systemic concentrations of other cytokines, including interleukin-1b (IL1b), remain unchanged in healthy elderly (6,7).…”

mentioning

confidence: 99%

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

Rutkute

Asmis

Nikolova‐Karakashian

2007

Journal of Lipid Research

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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-1b (IL-1b) 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-1b 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-1b, 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-1b response. Importantly, the GSH decline, NSMase activation, and IL-1b 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-1b by inducing NSMase-2 activity. Increased basal inflammation is a phenomenon emblematic of the aging process. It is characterized by increased concentrations of serum markers such as C-reactive protein and serum amyloid A (1) as well as by the activation of proinflammatory signaling molecules such as c-Jun N-terminal kinase (JNK) (2), nuclear factor-kB (NF-kB) (3), and CCAAT/enhancer binding proteins a and b (4). According to the oxidative stress hypothesis of aging, changes in mitochondrial functions and the deterioration of antioxidant defense mechanisms lead to an imbalance in the production and neutralization of free radicals, which in turn induces tissue damage and inflammation. Indeed, oxidative stress seems to play a fundamental role in the onset of aging-associated inflammation, because a decline in reactive oxygen species (ROS) generation brought about by calorie restriction (5) or by antioxidant supplementation decreases the expression of various inflammatory markers in aged animals. It has been proposed that the excess ROS generated during aging stimulate the secretion of proinflammatory cytokines, thus creating a proinflammatory environment (5). However, despite the fact that basal levels of some cytokines, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), seem to increase with age, these increases are modest, and it is not yet clear whether they are sufficient to evoke an inflammatory response. Moreover, the systemic concentrations of other cytokines, including interleukin-1b (IL1b), remain unchanged in healthy elder...

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mentioning

confidence: 99%

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

Rutkute

Asmis

Nikolova‐Karakashian

2007

Journal of Lipid Research

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“…10 Various IL-1␤-related functions, however, like the regulation of acute phase protein expression in liver, appear to be age dependent. Interestingly, the basal levels of acute phase reactants increase with age in a variety of species, from Drosophila melanogaster 11 to mammals, 1,12 and this has been linked to aging-related disorders, such as Alzheimer's disease, 13 rheumatoid arthritis, 1 and cardiovascular diseases.…”

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confidence: 99%

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

et al. 2007

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The process of aging has recently been shown to substantially affect the ability of cells to respond to inflammatory challenges. We demonstrate that aging leads to hepatic hyperresponsiveness to interleukin 1␤ (IL-1␤), and we examine the factors that could be responsible for this phenomenon. IL-1␤-induced phosphorylation of c-jun N-terminal kinase (JNK) in hepatocytes isolated from aged rats was 3 times more potent than that in hepatocytes from young rats. Moreover, JNK was activated by substantially lower doses of IL-1␤. These age-related changes in JNK phosphorylation correlated with diminished IL-1␤-induced degradation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Expression levels of IL1␤ receptor I, total JNK, IRAK-1, and transforming growth factor-␤-activated kinase-1 (TAK-1) were not affected by aging. However, increased neutral sphingomyelinase activity was observed in hepatocytes from old animals, which we show is caused by induction of the plasma membrane localized neutral sphingomyelinase-2 (NSMase-2). We provide evidence that NSMase-2 is both required and sufficient for the onset of IL-1␤ hyperresponsiveness during aging. Overexpression of NSMase-2 in hepatocytes from young rats leads both to a reduction in IRAK-1 degradation and potentiation of JNK phosphorylation, mimicking that seen in hepatocytes from old animals. More importantly, inhibition of NSMase activity in hepatocytes from aged rats using either scyphostatin or short interfering ribonucleic acid (siRNA) leads to reversion to the "young" phenotype of IL-1␤ response. Conclusion: These results show that the process of aging causes increased basal NSMase-2 activity in hepatocytes, which in turn leads to IRAK-1 stabilization, JNK potentiation, and ultimately IL-1␤ hyperresponsiveness. (HEPATOLOGY 2007;46:1166-1176

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“…IL-1β is secreted by a number of cell types into local environment and systemic circulation. Serum levels of IL-1β do not change significantly with aging [34]. Also, in vitro stimulation of RPE cells with Aβ resulted in increased IL-1β expression [16,35].…”

Section: Il-1βmentioning

confidence: 86%

Drusen and Pro-inflammatory Mediators in the Post-Mortem Human Eye

Jiang¹,

To²,

Cui³

et al. 2012

J Clinic Experiment Ophthalmol

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Serum IL-1β levels in health and disease: a population-based study. ‘The InCHIANTI study’

Cited by 98 publications

References 27 publications

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

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

Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2

Drusen and Pro-inflammatory Mediators in the Post-Mortem Human Eye

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