美國(guó)弗吉尼亞理工大學(xué)的Liwu Li副教授最近發(fā)現(xiàn),，在細(xì)胞先天性免疫網(wǎng)和人類慢性炎癥疾病（包括動(dòng)脈硬化,、2型糖尿病,、以及神經(jīng)退化性疾病等）之間存在一個(gè)普遍聯(lián)系,。這一發(fā)現(xiàn)為嚴(yán)重炎癥疾病的診斷和治療提供了可能的細(xì)胞和分子目標(biāo),。結(jié)果發(fā)表在九月份出版的愛(ài)思唯爾期刊《分子免疫學(xué)》（Molecular Immunology）上。
Li是弗吉尼亞理工大學(xué)炎癥研究中心奠基人,，他表示：“長(zhǎng)期以來(lái)科研人員和醫(yī)生都意識(shí)到在這些疾病之間存在某種聯(lián)系,，例如，肥胖將增加心臟病和中風(fēng),、2型糖尿病,、胰島素抵抗以及阿茲海默癥的風(fēng)險(xiǎn)。”
Li還認(rèn)為：“炎癥反應(yīng)是一種常見(jiàn)機(jī)制,，這是一把雙刃劍,，正確的炎癥反應(yīng)對(duì)于抵御感染入侵以及消除異常細(xì)胞是必要的。而另一方面,，過(guò)度的炎癥導(dǎo)致多種慢性疾病,。但是我們對(duì)于控制炎癥反應(yīng)的復(fù)雜細(xì)胞分子網(wǎng)了解的很少，這種了解的缺乏阻礙了治療方法的進(jìn)展。”
在過(guò)去發(fā)表的一系列文章中,，Li的小組確定了數(shù)個(gè)對(duì)于調(diào)節(jié)炎癥至關(guān)重要的信號(hào)網(wǎng),，而其中一種細(xì)胞蛋白激酶—白細(xì)胞介素-1受體相關(guān)激酶1（IRAK-1）對(duì)于處理多種炎癥信號(hào)都很重要，其中包括微生物產(chǎn)物,、細(xì)胞因子,、胰島素等。Li小組還發(fā)現(xiàn)過(guò)度的IRAK-1激活將導(dǎo)致動(dòng)脈硬化和糖尿病,。利用無(wú)IRAK-1基因的轉(zhuǎn)基因小鼠,，研究人員證明缺少IRAK-1能防止發(fā)生動(dòng)脈硬化以及胰島素抵抗。
在分子學(xué)水平上IRAK-1傾向于使轉(zhuǎn)錄因子磷酸化,，這導(dǎo)致STAT-3和NFAT參與到各種炎癥調(diào)節(jié)子的調(diào)節(jié)中,，這些調(diào)節(jié)子導(dǎo)致特異性的巨噬細(xì)胞、T細(xì)胞過(guò)度激活,。巨噬細(xì)胞,、T細(xì)胞最終產(chǎn)生各種炎癥癥狀。Li說(shuō)：“要徹底治愈這些疾病還有很長(zhǎng)的路要走,，這也是為何我們要聯(lián)合多學(xué)科專家的原因,，其中就包括實(shí)驗(yàn)生物學(xué)以及計(jì)算模擬專家。炎癥研究中心結(jié)合了實(shí)驗(yàn)分子生物學(xué)專家,、細(xì)胞和組織成像,、細(xì)胞信號(hào)網(wǎng)絡(luò)計(jì)算模擬、人類和動(dòng)物學(xué)研究,、以及納米技術(shù),。”（生物谷Bioon.com）
生物谷推薦原始出處：
Molecular Immunology，doi:10.1016/j.molimm.2008.06.023,，Dongmei Wang, Stephan Fasciano, and Liwu Li
The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT
Dongmei Wang1, a, Stephan Fasciano1, a and Liwu Li, a,
aThe Laboratory of Innate Immunity and Inflammation, Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, United States
Abstract
IRAK-1 is a critical modulator regulating innate immunity signaling processes. However, the physiological substrates for IRAK-1 remain poorly defined. In this report, we have demonstrated that IRAK-1 is a kinase responsible for the constitutive phosphorylation and inactivation of the Nuclear Factor of Activated T-cell (NFAT). Expression of IRAK-1 suppressed NFAT reporter activity. Correspondingly, the levels of both nuclear NFATc1 and NFATc4 were constitutively elevated in IRAK-1−/− cells. Furthermore, the phosphorylation of NFATc4 at the S168PS170P site was significantly diminished in IRAK-1−/− cells. Mechanistically, we observed that IRAK-1 interacted with NFATc4 via the C-terminus of IRAK-1 and the N-terminal NHR region of NFATc4. IRAK-1 mutants that ablated either its kinase activity or its interaction with NFATc4 failed to suppress NFAT reporter activity. The expression level of COX2, which is under the control of NFAT, was elevated in IRAK-1−/− cells. Functionally, ApoE−/−/IRAK-1−/− mice were protected from high-fat-diet-induced hypertension and atherosclerosis. Taken together, our findings reveal NFAT molecules as novel physiological targets for IRAK-1.
