CALL FOR PAPERS Epigenetics and Epigenomics S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages

Pfalzer AC, Choi SW, Tammen SA, Park LK, Bottiglieri T, Parnell LD, Lamon-Fava S. S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages. Physiol Genomics 46: 617–623, 2014. First published July 15, 2014; doi:10.1152/physiolgenomics.00056.2014.—S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokine TNFand 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 mol/l SAM for 24 h, followed by stimulation with LPS. TNF 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 mol/l SAM), treatment with 500 mol/l SAM caused a significant decrease in TNFexpression ( 45%, P 0.05) and increase in IL-10 expression ( 77%, P 0.05). Treatment with 1,000 mol/l SAM yielded no significant additional benefits. Relative to control, 500 mol/l SAM increased cellular SAM concentrations twofold without changes in SAH, and 1,000 mol/l SAM increased cellular SAM sixfold and SAH fourfold. Global DNA methylation increased 7% with 500 mol/l SAM compared with control. Following treatment with 500 mol/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.