Abstract
SET and MYND domain-containing 2 (Smyd2), a histone 3 lysine 4- and histone 3 lysine 36 (H3K36)-specific methyltransferase, plays critical roles in cardiac development and tumorigenesis. However, the role of Smyd2 in immunity and inflammation remains poorly understood. In this study, we report that Smyd2 is a novel negative regulator for macrophage activation and M1 polarization. Elevated Smyd2 expression suppresses the production of proinflammatory cytokines, including IL-6 and TNF, and inhibits the expression of important cell surface molecules, including major MHC-II and costimulatory molecules. Furthermore, macrophages with high Smyd2 expression inhibit Th-17 cell differentiation but promote regulatory T cell differentiation as a result of increased TGF-β production and decreased IL-6 secretion. In macrophages, Smyd2 specifically facilitates H3K36 dimethylation at Tnf and Il6 promoters to suppress their transcription and inhibits NF-κB and ERK signaling. Therefore, our data demonstrate that epigenetic modification by Smyd2-mediated H3K36 dimethylation at Tnf and Il6 promoters plays an important role in the regulation of macrophage activation during inflammation.
Highlights
Macrophages express SET and MYND domain-containing 2 (Smyd2) during development and differentiation
Smyd2 Expression Is Reduced following Macrophage Activation—In this study, mouse bone marrow cells were differentiated into mature macrophages (i.e. M0 macrophages) by macrophage colony stimulation factor (MCSF)
When Smyd2 expression during macrophage differentiation was analyzed, we found that there was no significant difference in Smyd2 transcription between bone marrow cells and differentiated M0 cells (Fig. 1B)
Summary
Macrophages express Smyd during development and differentiation. Results: Smyd inhibits macrophage IL-6 and TNF-␣ production. Our data demonstrate that epigenetic modification by Smyd2-mediated H3K36 dimethylation at Tnf and Il6 promoters plays an important role in the regulation of macrophage activation during inflammation. Marked changes in the activity and gene expression profile of macrophages can occur when stimulated by pathogens or related cytokines, and these changes are tightly regulated by genetic, epigenetic, and transcriptional modification [16, 17]. It has been reported that histone lysine methylation plays a critical role in macrophage polarization and activation. One report showed that H3K27 demethyltransferase Jumonji domain containing 3 (Jmjd3) plays a critical role in M2 macrophage activation [22], whereas another report suggested that H3K4 histone methyltransferase Ash1l with a conserved SET domain regulated IL-6 and TNF-␣ production in LPS-induced macrophage activation [23]. Our study is important for understanding the regulation of macrophage polarization and provides new insights for autoimmune disease therapy
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