近日,，來(lái)自第二軍醫(yī)大學(xué)醫(yī)學(xué)免疫學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室,、上海海洋大學(xué)等處的研究人員發(fā)表了題為“Notch Signal Suppresses Toll-like Receptor-triggered Inflammatory Responses in Macrophages by Inhibiting Extracellular Signal-regulated Kinase 1/2-mediated Nuclear Factor κB Activation”的文章，提出了一種Toll樣受體途徑通過(guò)Notch信號(hào)通路進(jìn)行負(fù)調(diào)控的新機(jī)制,，這將有助于更深入了解Notch途徑與Notch信號(hào)通路的關(guān)聯(lián),，并且這種巨噬細(xì)胞炎癥應(yīng)答機(jī)制也為理解炎癥調(diào)控提出了一種新觀點(diǎn)。相關(guān)成果公布在《生物化學(xué)期刊》JBC雜志上,。
文章的通訊作者是第二軍醫(yī)大學(xué)曹雪濤院士以及李楠教授,，曹雪濤教授05年當(dāng)選中國(guó)工程院院士，主要從事腫瘤免疫治療和分子免疫學(xué)方面的研究,，以通訊作者在Nature Immunology,、Immunity、Blood,、J Immunol,，Cancer Res，J Biol Chem等SCI收錄的國(guó)外知名雜志上發(fā)表論文上百篇,。
Toll-like receptor（TLR）是免疫系統(tǒng)中的一類(lèi)重要分子,，參與了非特異性免疫（天然免疫），也是連接非特異性免疫和特異性免疫的橋梁,。研究證明TLR的嚴(yán)格調(diào)控包含了多個(gè)信號(hào)途徑,，這對(duì)于機(jī)體巨噬細(xì)胞對(duì)病原體作出炎癥應(yīng)答調(diào)控具有重要意義。
比如TLR能激活Notch途徑,，后者是進(jìn)化中高度保守的信號(hào)轉(zhuǎn)導(dǎo)通路,， 其調(diào)控細(xì)胞增殖、分化和凋亡的功能涉及幾乎所有組織和器官,。之前的研究還發(fā)現(xiàn)Notch信號(hào)通路在免疫系統(tǒng)的發(fā)育和功能方面也扮演了重要角色,，但是Notch信號(hào)完整通路是否能調(diào)控TLR信號(hào)途徑,，來(lái)控制炎癥應(yīng)答，這一點(diǎn)科學(xué)家們還并不清楚,。
在這篇文章中,，研究人員通過(guò)實(shí)驗(yàn)，證明TLR配基刺激能正調(diào)控Notch1和Notch2在巨噬細(xì)胞中的表達(dá),，Notch表達(dá)靶向的基因：Hes1和 Hes5,，在巨噬細(xì)胞中也可以由LPS誘導(dǎo)激活，這說(shuō)明TLR4信號(hào)能增強(qiáng)Notch途徑的活性,。
而且更重要的是,，Notch1（NICD1）和Notch2（NICD2）活性形式的過(guò)量表達(dá)，會(huì)抑制TLR4開(kāi)啟的炎癥細(xì)胞因子（比如TNF-α 和IL-6）的生成,，并且促進(jìn)抗炎癥細(xì)胞因子IL-10的生成,。
除此之外，NICD1和NICD2還能抑制TLR激活ERK磷酸化,，這是Notch介導(dǎo)的TLR4激活炎癥細(xì)胞因子生成,，不可或缺的組成部分，Notch信號(hào)途徑也能抑制NF-κB 轉(zhuǎn)錄活性,。
這些研究數(shù)據(jù)表明Notch信號(hào)能負(fù)調(diào)控TLR激活的炎癥應(yīng)答,，從而揭示出TLR途徑通過(guò)Notch途徑介導(dǎo)的一種負(fù)調(diào)控新機(jī)制。
曹雪濤教授研究組多年來(lái)在免疫學(xué)領(lǐng)域取得了各種重要成果,，除了免疫學(xué)領(lǐng)域，他們?cè)诎┌Y與miRNA研究方面也取得了不少進(jìn)展,，比如去年他們通過(guò)深度測(cè)序技術(shù)進(jìn)行人正常肝臟,、病毒性肝炎肝臟、肝硬化肝臟和人肝癌microRNA組學(xué)分析,，發(fā)現(xiàn)了microRNA-199表達(dá)高低與肝癌患者預(yù)后密切相關(guān),，證明microRNA-199能夠靶向抑制促肝癌激酶分子PAK4而顯著抑制肝癌生長(zhǎng)，從而為肝癌的預(yù)防判斷與生物治療提供了新的潛在靶標(biāo),。
研究人員先通過(guò)深度測(cè)序技術(shù)首次獲得了人正常肝臟,、病毒性肝炎肝臟、肝硬化肝臟和人肝癌組織的microRNA組數(shù)據(jù),，了解到肝癌與正常肝臟microRNA的差別,，通過(guò)4個(gè)獨(dú)立的肝癌患者臨床隊(duì)列分析，發(fā)現(xiàn)人正常肝臟高豐度表達(dá)的microRNA-199在人肝癌中普遍性顯著降低,，并且microRNA-199的低表達(dá)與肝癌患者的生存期降低顯著相關(guān),。進(jìn)一步發(fā)現(xiàn)肝癌組織中組蛋白甲基化改變導(dǎo)致了microRNA-199表達(dá)降低，microRNA-199能夠靶向抑制PAK4進(jìn)而抑制下游的ERK信號(hào)通路,，從而抑制了肝癌細(xì)胞的生長(zhǎng),。通過(guò)肝靶向性腺相關(guān)病毒載體介導(dǎo)的microRNA-199基因治療,，顯著延長(zhǎng)了肝癌裸鼠生存期。由此證明microRNA-199是肝癌預(yù)防判斷與治療新的潛在靶標(biāo),，為肝癌生物治療提出了新方法,。（生物谷Bioon.com）
doi:10.1074/jbc.M111.310375
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Notch Signal Suppresses Toll-like Receptor-triggered Inflammatory Responses in Macrophages by Inhibiting Extracellular Signal-regulated Kinase 1/2-mediated Nuclear Factor κB Activation*
Qinghua Zhang‡§,1, Chunmei Wang‡,1, Zhaolong Liu¶, Xingguang Liu‡, Chaofeng Han‡, Xuetao Cao‡,2 and Nan Li‡,3
Multiple signaling pathways are involved in the tight regulation of Toll-like receptor (TLR) signaling, which is important for the tailoring of inflammatory response to pathogens in macrophages. It is widely accepted that TLR signaling can activate Notch pathway; however, whether full activation of Notch signaling can feedback modulate TLR signaling pathway so as to control inflammation response remains unclear. Here, we demonstrated that stimulation with TLR ligands up-regulated Notch1 and Notch2 expression in macrophages. The expression of Notch target genes including Hes1 and Hes5 was also induced in macrophages by LPS, suggesting that TLR4 signaling enhances the activation of Notch pathway. Importantly, overexpression of constituted active form of Notch1 (NICD1) and Notch2 (NICD2) suppressed production of TLR4-triggered proinflammatory cytokines such as TNF-α and IL-6 but promoted production of antiinflammatory cytokine IL-10, which is dependent on the PEST domain of NICD. In addition, NICD1 and NICD2 suppressed TLR-triggered ERK phosphorylation, which is indispensable for Notch-mediated inhibition of TLR4-triggered proinflammatory cytokine production. Furthermore, activation of Notch signaling inhibited NF-κB transcription activity by MyD88/TRAF6 and TRIF pathways, which was dependent on ERK activity. Therefore, our results showed that Notch signaling negatively regulates TLR-triggered inflammation responses, revealing a new mechanism for negative regulation of TLR signaling via Notch pathway.
