Dataset Information

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

ABSTRACT: 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-?B; 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.

SUBMITTER: Yan Q

PROVIDER: S-EPMC4104139 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yan Qian Q Sun Lei L Zhu Ziyan Z Wang Lili L Li Shuqin S Ye Richard D RD

Cellular signalling 20140401 9

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 ...[more]

PMID: 24703936

Similar Datasets

Project description:RationaleStressful life events are suggested to contribute to the development of various pathologies, such as cardiovascular disorders, whose etiopathogenesis is highly associated with elevated levels of serum amyloid A (SAA) proteins. SAA synthesis in the liver is regulated by a complex network of cytokines acting independently or in concert with various hormones/stimulants including the stress-activated sympathetic nervous system.ObjectiveThis study aims to investigate the underlying mechanisms that regulate the stress-induced hepatic synthesis of SAA, with particular focus on adrenoceptors (AR), major components of the sympathoadrenal response to stress.Methods and resultsWe demonstrated that repeated stress elevates IL-1β, IL-6, and TNFα serum levels in mice, accompanied by increased synthesis and secretion of hepatic SAA1/2 and SAA3, an effect that was blocked by AR antagonists. Moreover, stimulation of α1- and β1/2-ARs mimics the stress effect on SAA1/2 regulation, whereas α2-AR stimulation exhibits a relatively weak impact on SAA. In support of the essential cytokine contribution in the AR-agonist induced SAA production is the fact that the anti-inflammatory drug, sodium salicylate, prevented the AR-stimulated hepatic SAA1/2 synthesis by reducing IL-1β levels, whereas IL-1β inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1β. Interestingly, the AR-driven SAA3 synthesis was elevated by sodium salicylate in a TNFα-dependent way, supporting diverse and complex regulatory roles of cytokines in SAA production. In contrast to α1/α2-AR, the β1/2-AR-mediated SAA1/2 and SAA3 upregulation cannot be reversed by fenofibrate, a hypolipidemic drug with anti-inflammatory properties.ConclusionTaken together, these findings strongly support a critical role of the AR-stimulated inflammatory response in the hepatic SAA production under stressful conditions, highlighting distinct AR type-specific mechanisms that regulate the hepatic synthesis of SAA1/2 and SAA3.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets