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Title: S-adenosylmethionine lowers the inflammatory response in macrophages associated with changes in DNA methylation

Author
item PFALZER, ANNA - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item CHOI, SANG WOON - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item TAMMEN, STEPHANIE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item PARK, LARA - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item BOTTIGLIERI, TEODORO - BAYLOR UNIVERSITY
item Parnell, Laurence
item LAMON-FAVA, STEFANIA - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/10/2014
Publication Date: 7/15/2014
Citation: Pfalzer, A., Choi, S., Tammen, S.A., Park, L.K., Bottiglieri, T., Parnell, L.D., Lamon-Fava, S. 2014. S adenosylmethionine lowers the inflammatory response in macrophages associated with changes in DNA methylation. Physiological Genomics. DOI: 10.1152/physiolgenomics.00056.2014.

Interpretive Summary: Inflammation plays a critical role in the initiation and progression of long-lasting conditions such as diabetes, heart disease, arthritis and depression. B vitamins, specifically B12 and B6, control production of a biochemical signals known as SAM (S-adenosylmethionine) such that deficiencies in these B vitamins may decrease SAM production and elevate the levels of another molecule known as homocysteine. High levels of homocysteine are often an indicator of systemic inflammation. Because of the role of SAM in inflammation and in regulating the active vs inactive state of genes, we examined treating macrophages, a type of cell commonly involved in the inflammation process, with SAM. We discovered that treating inflammatory macrophage cells with SAM was beneficial on two fronts: moderating signals that normally stimulate inflammation and decreasing the overall gene activity. SAM has important anti-inflammatory effects. Now science researchers can more fully understand the links between B vitamins, inflammation and common chronic diseases.

Technical Abstract: S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower inflammation. We assessed whether epigenetic mechanisms mediate this effect. Human THP-1 cells were differentiated into macrophages and treated with 0 micromole/L, 500 micromole/L or 1000 micromole/L SAM for 24 hours, followed by stimulation with LPS. TNF alphaand IL-10 expression levels were measured using real time-PCR. Cellular SAM and S-adenosylhomocysteine (SAH), a metabolite of SAM, were measured by LC-MS/MS. DNA methylation was measured using LC-MS/MS and microarrays. Relative to 0 micromole/L SAM, treatment with 500 micromole /L SAM caused a significant decrease in TNF alpha expression (-45%, p<0.05) and increase in IL-10 expression (+77%, p<0.05). Treatment with 1000 micromole /L SAM yielded no significant additional benefits. Relative to 0 micromole /L SAM, 500 micromole /L SAM treatment increased cellular SAM concentrations 2 fold without changes in SAH. Treatment with 1000 micromole /L SAM increased cellular SAM 6-fold and SAH 4-fold, relative to control. Global DNA methylation increased 7% with 500 micromole /L SAM supplementation compared to control. A DNA methylation microarray identified more than 700 differentially methylated regions associated with 918 genes with 500 micromole /L SAM, compared to control. Pathway analysis of these genes identified a biological network associated with cardiovascular disease. A sub-set of genes differentially methylated associated with altered expression levels. Our data indicate that SAM exerts significant anti-inflammatory effects through modulation of gene expression, possibly mediated by DNA methylation.