Epigenetic regulation of Il12 and Il23 gene expression and autoimmune inflammation by the deubiquitinase Trabid

The proinflammatory cytokines interleukin 12 (IL-12) and IL-23 connect innate and adaptive immune responses and are also involved in autoimmune and inflammatory diseases. Here we describe an epigenetic mechanism of Il12 and Il23 gene regulation involving the deubiquitinase Trabid. Deletion of Zranb1, the gene encoding Trabid, in dendritic cells inhibited the induction of IL-12 and IL-23 expression by Toll-like receptors (TLR), impairing the differentiation of inflammatory T cells and protecting mice from autoimmune inflammation. Trabid facilitated TLR-induced histone modifications at the Il12 and Il23 promoters, which involved deubiqutination and stabilization of the histone demethylase Jmjd2d. These findings highlight an epigenetic mechanism of Il12 and Il23 gene regulation and establish Trabid as an innate immune regulator of inflammatory T cell responses.