Ceramide Mediates Age-associated Increase in Macrophage Cyclooxygenase-2 Expression

Claycombe, Kate J.; Wu, Dayong; Nikolova‐Karakashian, Mariana; Palmer, Helen J.; Beharka, A.A.; Paulson, K. Eric; Meydani, Simin Nikbin

doi:10.1074/jbc.m204463200

Cited by 45 publications

(50 citation statements)

References 60 publications

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“…Finally, blocking NF-B activation reduced LPS-stimulated IL-6 and TNF-␣ production and SMaseinduced IL-6 production. Increased tissue ceramide content with aging has been reported (32)(33)(34)(35), but the mechanism underlying this phenomenon remains elusive. Cellular ceramide can be generated through the hydrolysis of sphingomyelin catalyzed by SMase or its de novo synthesis under action of several enzymes, including the rate-limiting SPT, from palmitoyl CoA and serine.…”

Section: Discussionmentioning

confidence: 99%

“…Because insulin resistance sharply increases with advancing age and low-grade inflammation in adipose tissue plays a key role in the development of insulin resistance, we hypothesized that aging is associated with increased adipose tissue inflammation. Furthermore, because both ceramide and NF-B are implicated in insulin resistance in insulin target cells as well as in age-associated up-regulation of inflammatory responses (19,(32)(33)(34)(35)(36)(37)(38)(39)(40), we conducted experiments to determine the role of ceramide and NF-B in age-associated adipose tissue inflammation.…”

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confidence: 99%

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Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

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The incidence of type 2 diabetes (T2D) increases with age. Low‐grade inflammation in AT is implicated in development of insulin resistance and T2D. We conducted a study to determine if inflammatory responses are upregulated with age in AT. Results show that visceral AT from old mice had significantly higher expression of mRNA levels of IL‐1β, IL‐6, TNF‐α, and COX‐2 than those of young mice (263, 208, 165, and 73%, higher respectively). In determining the relative contribution of different components of AT to these age‐related changes, we found that adipocytes (AD) from old mice produced significantly more (2 to 3 folds) IL‐6 and PGE2 than those from young mice while no significant age difference was observed in their production by stromal vascular cells. There was no significant effect of age on number of Mϕ/g AT and Mϕ of either age group produced significantly more IL‐6 when incubated in conditioned medium from old AD compared to that of young. Blocking NF‐κB activation reduced IL‐6 production while addition of ceramide or sphingomyelinase increased IL‐6 production in young AD to a level comparable to that of old AD. Inhibiting de novo ceramide synthesis reduced IL‐6 production by AD. NF‐κB regulates expression of inflammatory products including COX‐2 and IL‐6. Ceramide was shown to increase COX‐2 expression in aged Mϕ through NF‐κB activation. Thus, these data suggest a potential role for ceramide and NF‐κB in the age‐related increase of AT inflammation. Further research is needed to fully determine the underlying mechanisms of the observed effects and their contribution to T2D in the aged. Supported by USDA #58‐1950‐9‐001 and NIA #R01 AG009140‐10A1.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

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256

209

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“…Our recent study showed that the intracellular concentration of ceramide was higher in LPS-stimulated M of old mice compared with those of young mice and that this increased level of ceramide mediates the age-associated up-regulation of COX-2 transcription (14). Whereas the effect of ceramide on regulation of transcription factors has not been well defined, previous studies showed that ceramide induced AP-1 (28) and NFB activation (29).…”

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confidence: 96%

“…This increased COX activity is, in turn, a result of increased expression of COX-2 protein and mRNA (13). In a recent study, we further demonstrated that the age-related increase in COX-2 mRNA was because of a higher level of ceramide in old M compared with those of young, which induced up-regulation of COX-2 transcription (14). In addition, we showed that the effect of ceramide was not mediated through components of the mitogen-activated protein kinase pathway, c-Jun NH 2 -terminal kinase, extracellular signal-regulated kinase, or p38 (14).…”

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Ceramide-induced and Age-associated Increase in Macrophage COX-2 Expression Is Mediated through Up-regulation of NF-κB Activity

Wu¹,

Marko²,

Claycombe³

et al. 2003

Journal of Biological Chemistry

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104

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We have shown that the age-associated increase in lipopolysaccharide (LPS)-stimulated macrophages (M) prostaglandin E 2 (PGE 2 ) production is because of ceramide-induced up-regulation of cyclooxygenase (COX)-2 transcription that leads to increased COX-2 expression and enzyme activity. To determine the mechanism of the age-related and ceramide-dependent increase in COX-2 transcription, we investigated the role of various transcription factors involved in COX-2 gene expression. The results showed that LPS-initiated activations of both consensus and COX-2-specific NF-B, but not AP-1 and CREB, were significantly higher in M from old mice than those from young mice. We further showed that the higher NF-B activation in old M was because of greater IB degradation in the cytoplasm and p65 translocation to the nucleus. An IB phosphorylation inhibitor, Bay 11-7082, inhibited NF-B activation, as well as PGE 2 production, COX activity, COX-2 protein, and mRNA expression in both young and old M. Similar results were obtained by blocking NF-B binding activity using a NF-B decoy. Furthermore, NF-B inhibition resulted in significantly greater reduction in PGE 2 production and COX activity in old compared with young M. Addition of ceramide to the young M, in the presence or absence of LPS, increased NF-B activation in parallel with PGE 2 production. Bay 11-7082 or NF-B decoy prevented this ceramide-induced increase in NF-B binding activity and PGE 2 production. These findings strongly suggest that the age-associated and ceramide-induced increase in COX-2 transcription is mediated through higher NF-B activation, which is, in turn, because of a greater IB degradation in old M.It is well documented that T cell-mediated immune function declines in old animals and elderly humans compared with their young counterparts (1, 2). The age-associated dysregulation in macrophages (M) 1 contributes to the impaired T cell function with aging. We, as well as others, have demonstrated that immune cells, including M, from old animals and humans produced more PGE 2 than those from their young counterparts (3-7). We further showed that the increased PGE 2 production by M contributes to the decline in T cell-mediated function with aging (8).Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid (AA) to PG endoperoxide (PGH 2 ), which is further converted to different PGs and thromboxane. COX is hence a key factor in PG synthesis. Two isoforms of COX have been identified: a constitutive form, COX-1 (9, 10), and the inducible counterpart, COX-2 (11, 12). We have demonstrated that the age-associated increase in M PGE 2 production is because of higher COX activity in M from old mice compared with those from young mice. This increased COX activity is, in turn, a result of increased expression of COX-2 protein and mRNA (13). In a recent study, we further demonstrated that the age-related increase in COX-2 mRNA was because of a higher level of ceramide in old M compared with those of young, which induced up-regu...

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“…[6][7][8] Peritoneal macrophages, hepatocytes, and glial cells isolated from aged animals exhibit more severe and prolonged responses to inflammatory challenges compared with cells originating from young animals. [6][7][8][9] This hyperresponsiveness is manifested in altered activation patterns of cyclooxygenase-2, c-jun N-terminal kinase (JNK), nuclear factor kappa-B, CCAAT/enhancer binding protein alpha, and CCAAT/enhancer binding protein beta. Hence, changes in the cellular signaling pathways may contribute to the onset of the pro-inflammatory state in aging.…”

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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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Ceramide Mediates Age-associated Increase in Macrophage Cyclooxygenase-2 Expression

Cited by 45 publications

References 60 publications

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ceramide-induced and Age-associated Increase in Macrophage COX-2 Expression Is Mediated through Up-regulation of NF-κB Activity

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

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