11月，國(guó)際著名雜志Journal of Experimental Medicine在線發(fā)表了上海生科院/上海交大醫(yī)學(xué)院健康所免疫與疾病組最新研究論文,。
Th17作為一種近年來(lái)被發(fā)現(xiàn)的在炎癥性疾病和自身免疫疾病中起主導(dǎo)作用的效應(yīng)T細(xì)胞,，其產(chǎn)生的特征性細(xì)胞因子白介素17 (IL-17)越來(lái)越廣泛地受到關(guān)注。研究發(fā)現(xiàn)IL-17在多種自身免疫疾病如多發(fā)性硬化,，類(lèi)風(fēng)濕性關(guān)節(jié)炎,，牛皮癬的患者的特定病理組織中顯著上調(diào)。此外,，對(duì)于自身免疫疾病動(dòng)物模型研究表明IL-17或其受體IL-17R基因剔除小鼠能夠顯著抑制自身免疫疾病的誘導(dǎo),，而將IL-17抗體注射到小鼠體內(nèi)亦可以很大程度地減少自身免疫疾病的發(fā)生，表明阻斷IL-17的功能很可能會(huì)有效的治療自身免疫疾病,。因此,，研究IL-17發(fā)揮功能的信號(hào)轉(zhuǎn)導(dǎo)機(jī)制是至關(guān)重要的。錢(qián)友存等研究人員在之前的工作中闡明IL-17R與Act1和TRAF6形成復(fù)合體介導(dǎo)下游信號(hào)通路,。但是,，對(duì)于IL-17介導(dǎo)的信號(hào)通路如何被控制，相關(guān)研究幾乎還是空白,。
朱書(shū)博士在錢(qián)友存研究員的指導(dǎo)下研究發(fā)現(xiàn)了IL-17R信號(hào)通路的第一個(gè)負(fù)調(diào)節(jié)因子TRAF3,。該研究闡明TRAF3通過(guò)競(jìng)爭(zhēng)結(jié)合IL-17R影響了IL-17R–Act1–TRAF6信號(hào)復(fù)合物的形成，從而有效抑制IL-17信號(hào)轉(zhuǎn)導(dǎo)及其下游炎癥因子的誘導(dǎo),。進(jìn)一步研究證明TRAF3通過(guò)抑制IL-17信號(hào)通路控制了自身免疫腦脊髓炎EAE（多發(fā)性硬化的小鼠疾病模型）的發(fā)病,。該研究不僅拓寬了對(duì)于IL-17介導(dǎo)自身免疫疾病分子機(jī)制的認(rèn)識(shí)，并且為自身免疫疾病的治療提供了新的理論依據(jù)和潛在靶點(diǎn),。
該項(xiàng)目得到了國(guó)家自然科學(xué)基金,，國(guó)家科技部，中國(guó)科學(xué)院和上海市科委的資助,。（生物谷Bioon.com）
生物谷推薦英文摘要
JEM doi: 10.1084/jem.20100703
Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling
Shu Zhu1, Wen Pan1, Peiqing Shi1, Hanchao Gao1, Fang Zhao1, Xinyang Song1, Yan Liu1, Lihua Zhao1, Xiaoxia Li2, Yufang Shi1, and Youcun Qian1
Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17–induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17–induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.
