Ulcerative colitis (UC) is characterized by relapsing–remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3^−/−). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3^−/−. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.

溃疡性结肠炎（UC）的特征是复发缓解的炎症发作，并伴有不同的细胞因子水平，提示可能涉及表观遗传过程的转换。但是，对结肠炎中细胞因子水平的表观遗传学影响尚待探索。异二聚体白介素（IL）-12细胞因子家族在促炎和抗炎过程中均具有多种功能。最近报道了家族成员IL-35（EBI3 / IL-12p35）在UC中起抗炎作用。因此，我们旨在研究IL-35亚基在体外和体内的可能的表观遗传调控，并检查表观遗传靶向EBI3表达作为UC的治疗选择。暴露于促炎性TNFα或组蛋白脱乙酰基酶抑制剂（HDACi）会显着增加EBI3从健康组织产生的人结肠上皮细胞（HCEC）中的表达。当组合使用时，EBI3表达急剧上调，表明存在协同机制。结果，IL-35也增加。在体内，与未治疗的结肠炎小鼠相比，HDACi治疗的野生型小鼠的肠道表现出减少的结肠炎病理迹象。但是，在缺乏Ebi3的小鼠（Ebi3 ^-/-）中，完全丧失了HDACi治疗带来的改善。实际上，HDACi似乎加剧了Ebi3 ^-/-中的疾病表型。总之，我们的结果表明，在炎症条件下，EBI3通过组蛋白乙酰化的表观遗传机制被上调。体内数据表明，EBI3缺乏在结肠炎表现中起关键作用。相应地，我们的数据表明，促进组蛋白乙酰化的条件（例如在应用HDACi后）可通过涉及局部形成抗炎细胞因子IL-35的机制改善结肠炎。