Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-γ plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress

Komatsu, Wataru

doi:10.1016/s0891-5849(03)00027-3

Cited by 140 publications

(101 citation statements)

References 53 publications

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“…In this study, CLA's ability to elicit cytoprotective effects (enhanced cellular GSH and GCLS expression) at lower doses was shown for the first time, and this is in agreement with literature data showing the antiapoptotic effect of GCLC (45). In addition, our in vivo results showing CLA-induced upregulation of GSH via the enhanced expression of GCLC in vivo are consistent with recent findings showing the ability of other PPARg ligands to upregulate the expression of stress-responding enzymes and/or to enhance cellular redox status (23,46,47). NFnB activity has a critical role for T-cell maturation and in normal immune and inflammatory responses, and it is a pivotal transcription factor in the regulation of several cytokine genes, including IFNg and IL-10 (48).…”

Section: Discussionsupporting

confidence: 92%

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Bergamo

Luongo

Maurano

et al. 2006

Journal of Lipid Research

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Conjugated linoleic acid (CLA), a naturally occurring peroxisome proliferator-activated receptor g (PPARg) ligand, exhibits proapoptotic, immunomodulatory, and anticancer properties. In this study, we examined the biological effects of CLA administration in the MRL/MpJ-Fas lpr mouse, an animal model of systemic lupus erythematosus (SLE). We found that CLA exerted apparently opposed activities in in vitro experiments, depending on its concentration: 100 mM CLA downregulated IFNg synthesis and cell proliferation of splenocytes, in association with apoptosis induction and a decrease of intracellular thiols (GSH 1 GSSG), whereas 25 mM CLA did not significantly influence cell proliferation but enhanced the expression of g-glutamylcysteine ligase catalytic subunit (GCLC) and intracellular GSH concentration. Interestingly, the antiproliferative effect at 100 mM was not inhibited by the PPARg antagonist GW9662. In vivo, CLA administration drastically reduced SLE signs (splenomegaly, autoantibodies, and cytokine synthesis), a condition paralleled by the enhancement of GCLC expression and intracellular GSH content. Moreover, CLA administration significantly downregulated nuclear factor kB activity independent of PPARg activation and apoptosis induction. In conclusion, enhanced GSH content and GCLC expression in CLA-treated mice suggest a novel biochemical mechanism underlying its immunomodulatory activity and the beneficial effects on murine SLE signs.-Bergamo, P., D. Luongo, F. Maurano, G. Mazzarella, R. Stefanile, and M. Rossi. Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Fas lpr mice. J. Lipid Res.

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Section: Discussionsupporting

confidence: 92%

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Bergamo

Luongo

Maurano

et al. 2006

Journal of Lipid Research

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“…DHA is highly enriched in the neuronal or synaptic membrane (Salem, 1989), and its depletion can lead to increased n-6/ n-3 ratios, resulting in inflammation (De Caterina et al, 1994;Raederstorff et al, 1996;Simopoulos, 2002) or excessive oxidative stress (Komatsu et al, 2003), two conditions that enhance A␤ production (Sastre et al, 2003) and are present in AD and transgenic mice (Akiyama et al, 2000;Lim et al, 2000;Pratico et al, 2001;Grundman et al, 2002). Inflammatory cytokines and oxidative stress induce BACE expression and activity (Tamagno et al, 2002;Sastre et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, whereas ␣-secretase expression appears more or less constitutive (Sisodia, 1992;Lammich et al, 1999;Lopez-Perez et al, 2001), BACE1 expression in neuronal cells has been reported to be increased by both proinflammatory cytokines (Sastre et al, 2003) and oxidative damage (Tamagno et al, 2002). n-3 PUFAs have been reported to be antiinflammatory (De Caterina et al, 1994;Raederstorff et al, 1996;Simopoulos, 2002) and to reduce oxidative damage (Komatsu et al, 2003), consistent with protein carbonyl reduction with high-DHA diets (Calon et al, 2004). Therefore, BACE1 mRNA levels in animals on low-and high-DHA diets were analyzed by real- …”

Section: Bace Expression Was Unchanged By Dietary Pufamentioning

confidence: 94%

A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model

Lim¹,

Calon²,

Morita³

et al. 2005

J. Neurosci.

622

400

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Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. ␤-Amyloid (A␤) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total A␤ by Ͼ70% when compared with low-DHA or control chow diets. Dietary DHA also decreased A␤42 levels below those seen with control chow. Image analysis of brain sections with an antibody against A␤ (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40 -50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both ␣-and ␤-APP C-terminal fragment products and full-length APP. BACE1 (␤-secretase activity of the ␤-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against ␤-amyloid production, accumulation, and potential downstream toxicity.

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“…These results seem controversial but they may help to explain the discrepancy in the literature. Many studies observed a decrease in NO production by mice macrophages and cell lineages after exposure to FA [22][23][24][25], whereas others found an increase [27,34]. In addition to cell type and period of stimulation, these controversial results may be also due to the different concentrations of the FA used.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid control of nitric oxide production by macrophages

Lima

Scavone

et al. 2006

FEBS Letters

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Modulation of macrophage functions by fatty acids (FA) has been studied by several groups, but the effect of FA on nitric oxide production by macrophages has been poorly examined. In the present study the effect of palmitic, stearic, oleic, linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids on NF-jB activity and NO production in J774 cells (a murine macrophage cell line) was investigated. All FA tested stimulated NO production at low doses (1-10 lM) and inhibited it at high doses (50-200 lM). An increase of iNOS expression and activity in J774 cells treated with a low concentration of FA (5 lM) was observed. The activity of NF-jB was time-dependently enhanced by the FA treatment. The inhibitory effect of FA on NO production may be due to their cytotoxicity, as observed by loss of membrane integrity and/or increase of DNA fragmentation in cells treated for 48 h with high concentrations. The results indicate that, at low concentrations FA increase NO production by J774 cells, whereas at high concentrations they cause cell death.

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Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-γ plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress

Cited by 140 publications

References 53 publications

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model

Fatty acid control of nitric oxide production by macrophages

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