紐約大學(xué)Lu和同事們發(fā)現(xiàn)Auf1缺陷型小鼠表現(xiàn)出嚴(yán)重的內(nèi)毒素血癥,。深入地研究發(fā)現(xiàn)這是由TNFα,、IL-1β的mRNA穩(wěn)定性增加造成的,。文章作者指出,人類部分炎癥疾病可能源于損傷的轉(zhuǎn)錄后調(diào)控,。該研究成果發(fā)表在11月15日的《Genes & development》雜志上,。
在肌體中,促炎癥細(xì)胞因子的表達(dá)是受到嚴(yán)格調(diào)控的,,如果不正常表達(dá)會導(dǎo)致膿毒性休克(septic shock,,見備注1)。調(diào)節(jié)mRNA的穩(wěn)定性是調(diào)控它們表達(dá)的一個關(guān)鍵點(diǎn),。該穩(wěn)定性受3'非翻譯區(qū)的富AU元件(ARE)影響,。ARE引起轉(zhuǎn)錄產(chǎn)物不穩(wěn)定。Jin-Yu Lu和同事們通過研究發(fā)現(xiàn),,缺乏ARE結(jié)合蛋白之一Auf1蛋白的小鼠會提高TNFα和IL-1β的表達(dá),,并且非常容易患有內(nèi)毒素休克(endotoxic shock,;見備注2)1。Lu等人在缺乏Auf1的小鼠身上引入細(xì)菌性脂多糖內(nèi)毒素,,這種內(nèi)毒素會刺激全身炎癥反應(yīng)(systemic inflammatory response),。與大多數(shù)野生型小鼠順利度過這個難關(guān)相比,Auf1缺陷型小鼠表現(xiàn)出嚴(yán)重的內(nèi)毒素血癥(Endotoxemia,,ETM),,以及超出5倍的死亡率。這種TNFα 和 IL-1β的表達(dá)量增加是由mRNA穩(wěn)定性異常引起的,。有趣的是,,IL-6的mRNA穩(wěn)定性不受此影響,這可能是因為它的3'區(qū)域AREs構(gòu)造有所不同,。最后,,Lu等人進(jìn)一步研究發(fā)現(xiàn),使用抗體中和TNFα 和 IL-1β可以有效保護(hù)Auf1缺陷型小鼠,,使其不發(fā)生內(nèi)毒素休克,。文章作者指出,人類部分炎癥疾病可能源于損傷的轉(zhuǎn)錄后調(diào)控,。
深入閱讀:
1 J. Y. Lu, N. Sadri, and R. J. Schneider, Genes & development 20 (22), 3174 (2006).
Lab: Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
見備注:
1.膿毒性休克(septic shock)是指膿毒癥病人經(jīng)足量液體復(fù)蘇仍持續(xù)低血壓(收縮壓<90mmHg或較基礎(chǔ)水平下降幅度超過40mmHg),,伴有低灌流狀態(tài)(乳酸性酸中毒,少尿或急性意識改變)或器官功能障礙,。
2.內(nèi)毒素休克(endotoxic shock)在臨床上極為多見,。休克早期、由于細(xì)菌毒素對呼吸中樞的直接刺激或有效循環(huán)血量降低的反射刺激,,可引起呼吸增快,、換氣過度,導(dǎo)致呼吸性堿中毒,;繼而因臟器缺氧和血液不足,,生物氧化過程障礙,線粒體三羧酸循環(huán)受抑制,,ATP生成減少,,乳酸形成增多,導(dǎo)致代謝性酸中毒,,呼吸深大而快,。休克晚期、可因肺,、腦等臟器功能損害,,導(dǎo)致呼吸性酸中毒,出現(xiàn)呼吸幅度和節(jié)律改變,,使病變趨于不可逆,,可引起低血壓休克,、組織臟器灌注不足、代謝性酸中毒,、多器官功能不全,甚至多器官功能衰竭(MOF),。
英文原文:
Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs
Excessive production of proinflammatory cytokines, particularly tumor necrosis factor- (TNF) and interleukin-1 (IL-1), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia). Precise control of cytokine expression depends on rapid degradation of cytokine mRNAs, mediated by an AU-rich element (ARE) in the 3' noncoding region and by interacting ARE-binding proteins, which control the systemic inflammatory response. To understand the function of the ARE-binding protein AUF1, we developed an AUF1 knockout mouse. We show that AUF1 normally functions to protect against the lethal progression of endotoxemia. Upon endotoxin challenge, AUF1 knockout mice display symptoms of severe endotoxic shock, including vascular hemorrhage, intravascular coagulation, and high mortality, resulting from overproduction of TNF and IL-1. Overexpression of these two cytokines is specific, and shown to result from an inability to rapidly degrade these mRNAs in macrophages following induction. Neutralizing antibodies to TNF and IL-1 protect AUF1 knockout mice against lethal endotoxic shock. These and other data describe a novel post-transcriptional mechanism whereby AUF1 acts as a crucial attenuator of the inflammatory response, promoting the rapid decay of selective proinflammatory cytokine mRNAs following endotoxin activation. Defects in the AUF1 post-transcriptionally controlled pathway may be involved in human inflammatory disease.