近日，由中国工程院院士曹雪涛带领的团队揭示了炎症与自身免疫疾病发生的新机制，为防治人类自身免疫疾病提供了潜在新型靶点。该成果日前发表于《免疫》。
类风湿性关节炎等自身免疫性疾病是严重危害人类健康、影响生活质量的慢性炎症性疾病，目前临床上仍缺少对该病的根治性疗法。因此，人们对于炎症性自身免疫性疾病发生发展机制的研究非常关注，希望能为该病防治药物的研发提供新机制、新靶点、新方向。
近年来，研究发现，异常的组蛋白修饰与人类重大疾病，如肿瘤、心血管疾病、自身免疫性疾病等发病密切相关，逐渐成为热门的疾病诊断与治疗新靶点。
为此，曹雪涛团队将表观遗传修饰、炎症与天然免疫应答调控、自身免疫疾病发生发展机制联系起来开展研究，与浙江大学医学院免疫研究所、第二军医大学医学免疫国家重点实验室博士生夏梦、刘娟等通过小RNA干扰普筛实验发现，在所筛选的14种H3K4（去）甲基化转移酶中，H3K4甲基化转移酶Ash1l可以明显地负向调控巨噬细胞中病原体刺激触发的炎症性细胞因子——白细胞介素6的产生。
他们与复旦大学发育生物学研究所教授吴晓晖、许田合作，通过研究Ash1l缺陷小鼠进一步发现，老龄Ash1l缺陷小鼠器官中侵润更多炎性细胞，其体内存在高水平白细胞介素6，更易自发产生自身免疫性疾病并伴发器官组织的炎性损害。这表明Ash1l分子可以阻止炎症性自身免疫性疾病的发生发展。分子机制研究证明，Ash1l通过其H3K4甲基化转移酶活性，诱导了抑制性因子A20的表达，通过A20对炎症信号分子NEMO和TRAF6去泛素化作用，从而抑制下游MAPK和NF-κB炎症信号通路及随后白细胞介素6的表达，进而抑制自身免疫疾病的发生。(生物谷Bioon.com)
生物谷推荐的英文摘要
Immunity http://dx.doi.org/10.1016/j.immuni.2013.08.016
Histone Methyltransferase Ash1l Suppresses Interleukin-6 Production and Inflammatory Autoimmune Diseases by Inducing the Ubiquitin-Editing Enzyme A20
Meng Xia,Juan Liu, Xiaohui Wu, Shuxun Liu, Gang Li, Chaofeng Han, Lijun Song, Zhiqing Li, Qingqing Wang, Jianli Wang, Tian Xu, Xuetao Cao
Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-κB, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-κB signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.
