title: S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages.
abstract: S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokine TNF-α and increase the expression of the anti-inflammatory cytokine IL-10 in macrophages. The aim of this study was to assess whether epigenetic mechanisms mediate the anti-inflammatory effects of SAM. Human monocytic THP1 cells were differentiated into macrophages and treated with 0, 500, or 1,000 μmol/l SAM for 24 h, followed by stimulation with LPS. TNFα and IL-10 expression levels were measured by real-time PCR, cellular concentrations of SAM and S-adenosylhomocysteine (SAH), a metabolite of SAM, were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and DNA methylation was measured with LC-MS/MS and microarrays. Relative to control (0 μmol/l SAM), treatment with 500 μmol/l SAM caused a significant decrease in TNF-α expression (-45%, P < 0.05) and increase in IL-10 expression (+77%, P < 0.05). Treatment with 1,000 μmol/l SAM yielded no significant additional benefits. Relative to control, 500 μmol/l SAM increased cellular SAM concentrations twofold without changes in SAH, and 1,000 μmol/l SAM increased cellular SAM sixfold and SAH fourfold. Global DNA methylation increased 7% with 500 μmol/l SAM compared with control. Following treatment with 500 μmol/l SAM, DNA methylation microarray analysis identified 765 differentially methylated regions associated with 918 genes. Pathway analysis of these genes identified a biological network associated with cardiovascular disease, including a subset of genes that were differentially hypomethylated and whose expression levels were altered by SAM. Our data indicate that SAM modulates the expression of inflammatory genes in association with changes in specific gene promoter DNA methylation.
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, and.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pfalzer
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, and.
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, and.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Tammen
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, and.
authors.forename: Lara K
authors.initials: LK
authors.lastname: Park
authors.affiliation: Baylor Research Institute, Dallas, Texas.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, and stefania.lamon-fava@tufts.edu.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamon-Fava
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics; D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine
keywords: DNA methylation; S-adenosylhomocysteine; S-adenosylmethionine; inflammation; macrophage