中國工程院院士曹雪濤研究團隊在最新的研究中,，揭示了炎癥與自身免疫疾病發(fā)生新機制，發(fā)現(xiàn)了組蛋白甲基化轉(zhuǎn)移酶Ash1l能夠通過表觀調(diào)控機制抑制炎癥性細胞因子--白細胞介素6的產(chǎn)生而阻止炎性自身免疫疾病的發(fā)生發(fā)展,。
為未來防治人類自身免疫疾病提供了潛在的新型靶點,。9月21日，相關研究成果發(fā)表于《免疫》（Immunity）雜志,。
類風濕性關節(jié)炎等自身免疫性疾病是嚴重危害人類健康與影響生活質(zhì)量的慢性炎癥性疾病,，目前臨床上仍然缺少根治性療法，因此,，人們對于炎癥性自身免疫性疾病發(fā)生發(fā)展機制的研究非常關注,，期盼能夠為該病防治藥物的研發(fā)提供新機制新靶點新方向。
異常的組蛋白修飾與人類重大疾病如腫瘤,、心血管疾病,、自身免疫性疾病等發(fā)病密切相關，逐漸成為近年來非常熱門的疾病診斷與治療的新靶點,。
針對目前組蛋白修飾在天然免疫與炎癥,、尤其是在自身免疫性疾病發(fā)病過程中的作用尚不十分清楚的狀況，曹雪濤團隊將表觀遺傳修飾,、炎癥與天然免疫應答調(diào)控,、自身免疫疾病發(fā)生發(fā)展機制聯(lián)系起來開展研究，與浙江大學醫(yī)學院免疫研究所,、第二軍醫(yī)大學醫(yī)學免疫國家重點實驗室的博士生夏夢,、劉娟等通過小RNA干擾普篩實驗發(fā)現(xiàn)，在所篩選的14種H3K4（去）甲基化轉(zhuǎn)移酶中,，H3K4甲基化轉(zhuǎn)移酶Ash1l可以明顯地負向調(diào)控巨噬細胞中病原體刺激觸發(fā)的炎癥性細胞因子--白細胞介素6的產(chǎn)生,。
他們與復旦大學發(fā)育生物學研究所吳曉暉、許田教授合作,，通過制備的Ash1l缺陷小鼠進一步研究發(fā)現(xiàn),，老齡Ash1l缺陷小鼠器官中侵潤更多炎性細胞，其體內(nèi)存在高水平白細胞介素6,，更易自發(fā)產(chǎn)生自身免疫性疾病并伴發(fā)器官組織的炎性損害,，表明Ash1l分子可以阻止炎癥性自身免疫性疾病的發(fā)生發(fā)展。分子機制研究證明,，Ash1l通過其H3K4甲基化轉(zhuǎn)移酶活性誘導了抑制性因子A20的表達,，通過A20對炎癥信號分子NEMO和TRAF6去泛素化作用，從而抑制下游MAPK和NF-κB炎癥信號通路及隨后白細胞介素6的表達,，進而抑制自身免疫疾病的發(fā)生,。
該項研究得到國家973免疫學項目和國家基金委重點項目的資助。（生物谷 Bioon.com）
生物谷推薦的英文摘要
Immunity DOI: 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
Highlights
Ash1l attenuates inflammatory autoimmune disease by suppressing IL-6 production
Ash1l suppresses TLR-induced IL-6 production by enhancing A20 via SET domain
Ash1l facilitates H3K4 modification at Tnfaip3 promoter to induce its expression
Ash1l impairs TLR signaling by promoting A20-mediated NEMO and TRAF6 deubiquitination
Summary
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.
