Epigenetic Regulation Of Proinflammatory Genes Production In Serum Amyloid A-activated Macrophages

Serum amyloid A (SAA), a major acute-phase protein, has potent cytokine-likeactivities in isolated phagocytes and synovial fibroblasts. Although activation oftranscription factors such as NF-B is important to SAA-induced proinflammatorycytokine gene expression, little is known about its epigenetic regulation. Here wereport that Jmjd3, a histone H3lysine27(H3K27) demethylase, is highly inducible(9.8-fold up) in SAA-stimulated mouse bone marrow-derived macrophages (BMDM),primary peritoneal macrophages, and the RAW264.7macrophage cell line.SAA-induced Jmjd3expression leads to a reduction in H3K27trimethylation. InRAW264.7cells, silencing of Jmjd3expression by short hairpin RNA (shRNA) orco-transfection with an inactive mutant of Jmjd3significantly inhibited SAA-inducedexpression of proinflammatory cytokines including IL-23p19, G-CSF and TREM-1,along with up-regulation of H3K27trimethylation levels on their promoters.Depletion of Jmjd3expression also attenuated the release of proinfammatorycytokine genes in a peritonitis model and ameliorated neutrophilia in SAA-stimulatedmice. Finally, we observed that Jmjd3is essential for SAA-enhanced macrophagefoam cell formation by oxidized LDL. Taken together, these results illustrateJmjd3-dependent epigenetic regulation of proinfammatory cytokine gene expressionin SAA-stimulate macrophages, which may be subject to therapeutic intervention fordrug treatment of sterile inflammation and atherosclerosis.