Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages

• Published in: Cellular signalling Vol. 26; no. 9; pp. 1783 - 1791
• Main Authors: Yan, Qian, Sun, Lei, Zhu, Ziyan, Wang, Lili, Li, Shuqin, Ye, Richard D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.09.2014
• Subjects: Animals; Bone Marrow Transplantation; Cell Line; Cellular; Cytokines; Cytokines - genetics; Cytokines - metabolism; Epigenesis, Genetic; Extracellular Signal-Regulated MAP Kinases - metabolism; Foams; Gene expression; Gene Expression Regulation - drug effects; Genes; Histone demethylase; Histones; Histones - metabolism; Humans; Jmjd3; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Lipoproteins, LDL - toxicity; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Methylation - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Serum amyloid A; Serum Amyloid A Protein - toxicity; Serums; Sterile inflammation; HDACs; IL-12p35; CXCL1; FPR2; HMGB1; Macrophages; DAMPs; PI3K; PMs; oxLDL; TGF-β; BMDMs; PAMPs; TREM-1/2; IL-12p40; IL-1β; IL-8; MAPK; G-CSF; Serum amyloid A; SAA; Jmjd3; TNF-α; HATs; Histone demethylase; Sterile inflammation; H3K27me3; IL-23p19; ERK
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2014.03.025

Serum amyloid A (SAA), a major acute-phase protein, has potent cytokine-like activities in isolated phagocytes and synovial fibroblasts. SAA-induced proinflammatory cytokine gene expression requires transcription factors such as NF-κB; however, the associated epigenetic regulatory mechanism remains unclear. Here we report that Jmjd3, a histone H3 lysine 27 (H3K27) demethylase, is highly inducible in SAA-stimulated macrophages and plays an important role in the induction of inflammatory cytokine genes. SAA-induced Jmjd3 expression leads to reduced H3K27 trimethylation. Silencing of Jmjd3 expression significantly inhibited SAA-induced expression of proinflammatory cytokines including IL-23p19, G-CSF and TREM-1, along with up-regulation of H3K27 trimethylation levels on their promoters. Depletion of Jmjd3 expression also attenuated the release of proinflammatory cytokine genes in a peritonitis model and ameliorated neutrophilia in SAA-stimulated mice. Finally, we observed that Jmjd3 is essential for SAA-enhanced macrophage foam cell formation by oxidized LDL. Taken together, these results illustrate a Jmjd3-dependent epigenetic regulatory mechanism for proinflammatory cytokine gene expression in SAA-stimulate macrophages. This mechanism may be subject to therapeutic intervention for sterile inflammation and atherosclerosis. [Display omitted] •SAA induces Jmjd3 expression in macrophages.•Elevated Jmjd3 expression leads to reduced trimethylation at Lys-27 in Histone H3.•Silencing of Jmjd3 abrogates SAA-induced cytokine gene expression and neutrophilia.•Jmjd3 provides an epigenetic regulatory mechanism for SAA-induced gene expression.