Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages.
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.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Qian
Q
Yan
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Lei
L
Sun
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Ziyan
Z
Zhu
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Lili
L
Wang
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Shuqin
S
Li
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China; Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, United States. Electronic address: yedequan@sjtu.edu.cn.
Richard D
RD
Ye
D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000633:toxicity*
D016207:Cytokines; D006657:Histones; D008077:Lipoproteins, LDL; D053594:Myeloid Differentiation Factor 88; D000685:Serum Amyloid A Protein; C099252:oxidized low density lipoprotein; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
Histone demethylase; Jmjd3; Macrophages; Serum amyloid A; Sterile inflammation