Histone methyltransferase Smyd2 is a negative regulator of macrophage activation by suppressing IL-6 and TNF-{alpha} production [Immunology]

January 12th, 2015 by Xu, G., Liu, G., Xiong, S., Liu, H., Chen, X., Zheng, B.

SET and MYND domain containing-2 (Smyd2), a H3K4 and 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 pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF), and inhibits the expression of important cell-surface molecules, including major histocompatibility complex class II (MHC-II) and co-stimulatory molecules. Furthermore, macrophages with high Smyd2 expression inhibit Th-17 cell differentiation but promote regulatory T cell (Treg) differentiation as a result of increased transforming growth factor beta (TGF-β) production and decreased IL-6 secretion. In macrophages, Smyd2 specifically facilitates H3K36 di-methylation 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 di-methylation at Tnf and Il6 promoters plays an important role in the regulation of macrophage activation during inflammation.