Progress 10/01/02 to 06/30/07
Outputs
The overall goal of this project is to study the mechanisms of anti-inflammatory action of ecosapentaenoic acid (EPA), one of the two major n-3 fatty acids in fish oil. Many studies have shown that fish oil supplementation inhibits tumor necrosis factor-alpha (TNF-alpha) production in mice and humans, however, the mechanisms remain unclear. Nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) are transcription factors which play an important role in regulating the expression of pro-inflammatory genes including TNF-alpha. In this study, the effects of eicosapentaenoic acid (EPA) on lipopolysaccharide (LPS)-induced TNF-alpha production and DNA binding of NF-kB and AP-1 were investigated in human monocytic THP-1 cells. The cells were pre-treated with or without EPA, then incubated with LPS. The results showed that EPA partially prevented LPS-induced TNF-alpha production and DNA binding of NF-kB. EPA also partially prevented LPS-induced translocation of p65 subunit of
NF-kB to the nucleus, LPS-induced degradation of IkB-alpha and LPS-mediated IkB-alpha phosphorylation. The results also demonstrated that EPA partially prevented DNA binding of AP-1. LPS-induced phosphorylation of c-Jun (a component of AP-1) and activation of c-Jun terminal kinase (JNK) were also partially suppressed by EPA pre-treatment. The results suggest that suppression of TNF-alpha production, thus suppression of inflammation, by EPA is partly mediated by its preventive effect on DNA binding of NF-kB and AP-1.
Impacts
The research project provides the molecular mechanisms underlying the anti-inflammatory effects of omega-3 (n-3) fatty acids. The mechanisms involve suppression of oxidative stress-sensitive nuclear transcription factors responsible for the production of mediator for inflammatory response. It appears that taking fish oil supplements or ingestion of fatty fish can modulate inflammatory response which is involved in pathophysiology of many human diseases.
Publications
- No publications reported this period
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Progress 01/01/05 to 12/31/05
Outputs
The overall goal of this project is to study the mechanisms of anti-inflammatory action of eicosapentaenoic acid (EPA), one of the two major n-3 polyunsaturated fatty acids in fish oil. Studies have shown that fish oil supplementation decreases the secretion of tumor necrosis factor-alpha (TNF-alpha, a mediator for inflammatory response) in animals and humans, however, the mechanisms are not clear. NF-kB is a nuclear transcription factor which plays an important role in regulating the expression of pro-inflammatory genes including TNF-alpha. In an animal study, the effect of dietary fish oil on LPS-induced NF-kB activation was studied in the liver of rats after 8 weeks of feeding period. The results showed that dietary fish oil, when compared to corn oil, markedly suppressed LPS-induced NF-kB activation. In order to study the mechanism, human monocytic THP-1 cell culture system was used. Among various types of fatty acids, both n-3 fatty acids, EPA and docosahexaenoic
acid (DHA), suppressed the secretion of TNF-alpha to the highest degree. The LPS-induced activation of NF-kB was suppressed by EPA. The LPS-induced translocation of p65 subunit of NF-kB to the nucleus was inhibited by EPA. In addition, LPS-induced degradation of IkB-alpha and LPS-mediated IkB-alpha phosphorylation in the cytosol, were inhibited by EPA. The results suggest that the inhibitory effect of fish oil on TNF-alpha secretion is partly mediated by the inhibitory effect of n-3 polyunsaturated fatty acids on NF-kB activation via inhibition of IkB-alpha phosphorylation.
Impacts
The research project continues to provide basic information how omega-3 (n-3) fatty acids exert anti-inflammatory effect. Since the pathology of many diseases involves inflammation (including cardiovascular disease and arthritis), a dietary recommedation can be made that people should consume deep ocean fish or take fish oil supplementation.
Publications
- Zhao, Y. and Chen, L.H. 2005. Eicosapentaenoic acid prevents lipopolysaccharide-stimulated DNA binding of activator protein-1 and c-Jun N-terminal kinase activity. J. Nutr. Biochem. 16:78-84.
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Progress 01/01/04 to 12/31/04
Outputs
The overall goal of this project is to study the mechanisms of anti-inflammatory action of ecosapentaenoic acid (EPA), one of the two major n-3 fatty acids in fish oil. Tumor necrosis factor-alpha (TNF-alpha) is a mediator of inflammatory processes. Many studies have shown that fish oil supplementation inhibits TNF-alpha production in mice and humans, however, the mechanisms remain unclear. Activator protein-1 (AP-1) is a transcription factor that plays an important role in regulating the expression of the genes of pro-inflammatory cytokines, including TNF-alpha. In this study, the effects of EPA on the expression of TNF-alpha and the activation of AP-1 were investigated in human monocytic THP-1 cells. Cells were pre-incubated with or without EPA and stimulated with lipopolysaccharide (LPS). The results demonstrated that both LPS-induced TNF-alpha production and TNF-alpha mRNA levels were significantly decreased in cells pre-incubated with EPA. DNA binding activity of
LPS-stimulated AP-1 and increase of c-Jun and c-Fos proteins (components of AP-1) were also attenuated by EPA. Phosphorylation of c-Jun by c-Jun N-terminal kinase (JNK) increases the ability for transcriptional activation. Our results further showed that both LPS-induced phosphorylation of c-Jun and activation of JNK were suppressed by EPA. The results suggest that the suppression of TNF-alpha expression by EPA is partly mediated by its inhibitory effect on the activation of AP-1.
Impacts
The research program provides information how an omega-3 (n-3) fatty acid in fish oil works as an anti-inflammatory agent. Since the pathology of many diseases, such as cardiovascular disease and inflammatory bowl disease, involves inflammatory processes, it is beneficial to increase the consumption of fish or take fish oil supplementation.
Publications
- Zhao, Y., Joshi-Barve, S., Barve, S. and Chen, L.H. 2004. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. Journal of American Coll. Nutrition. 23:71-78.
- Zhao, Y. and Chen, L.H. 2005. Eicosapentaenoic acid prevents lipopolysaccharide-stimulated DNA binding of activator protein-1 and c-Jun N-terminal kinase activity. Journal of Nutritional Biochemistry. In press.
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Progress 01/01/03 to 12/31/03
Outputs
Many studies have shown that fish oil supplementation decreases tumor necrosis factor-alpha (TNF-alpha) production in mice and human subjects; however, the mechanisms remain unclear. TNF-alpha is a mediator of inflammatory processes. Nuclear factor-kB (NF-kB) is a transcription factor that plays an important role in controlling the expression of inflammatory genes including TNF-alpha. In this study, the effects of eicosapentaenoic acid (EPA), a major n-3 fatty acid in fish oil, on the expression of TNF-alpha and the activation of NF-kB were investigated in human monocytic THP-1 cells. Cells were pre-incubated with EPA and stimulated with lipopolysaccharide (LPS). The results showed that both LPS-induced TNF-alpha production and TNF-alpha mRNA levels were significantly decreased in cells pre-incubated with EPA. LPS-induced NF-kB activation was slightly inhibited by pre-treating cells with EPA. Meanwhile, LPS-induced phosphorylation of IkB-alpha was significantly
suppressed and LPS-induced decrease of IkB-alpha was slightly inhibited by EPA. Therefore, EPA might affect NF-kB activation by inhibiting IkB-alpha phosphorylation. The results demonstrated that the suppression of TNF-alpha expression by EPA may be partly mediated by its inhibitory effect on NF-kB activation.
Impacts
The findings of this research project suggest that EPA or fish oil supplementation or fish consumption has an anti-inflammatory effect by partially suppressing the production of a mediator of inflammatory processes.
Publications
- Chen, L.H., Thielen, V., Cicci, R. and Langlais, P.J. 2003. Effects of chronic alcohol consumption and thiamin deficiency on antioxidant defenses in heart and skeletal muscle of rats. Alcohol Res. 8: 107-111.
- Zhao, Y. and Chen, L.H. 2003. N-3 polyunsaturated fatty acids/eicosanoids and inflammatory responses. In: Essential Fatty Acids and Eicosanoids: Invited Papers from 5th International Congress. Editors: Huang, Y.S., Li, S.J. and Huang, P.C., AOCS Press: Champaign, IL, pp. 219-226.
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