來(lái)自南開(kāi)大學(xué)生命科學(xué)學(xué)院,、美國(guó)康奈爾大學(xué)的研究人員發(fā)表了題為“Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression”，揭示了一條抑制動(dòng)脈粥樣硬化形成的新分子信號(hào)途徑。相關(guān)成果發(fā)布在近期的《生物化學(xué)雜志》（JBC）上,。
南開(kāi)大學(xué)的韓際宏(Jihong Han)教授與段亞君(Yajun Duan)為這篇論文的共同通訊作者,。韓際宏現(xiàn)為南開(kāi)大學(xué)生命科學(xué)學(xué)院特聘教授,、973計(jì)劃首席科學(xué)家,、長(zhǎng)江學(xué)者特聘教授。主要研究領(lǐng)域?yàn)閯?dòng)脈粥樣硬化成病機(jī)理與治療,；膽固醇及脂質(zhì)代謝信號(hào)通路,。
動(dòng)脈粥樣硬化（atherosclerosis）是動(dòng)脈硬化血管病中最常見(jiàn)的一種,，其特點(diǎn)是大、中動(dòng)脈內(nèi)膜出現(xiàn)含膽固醇,、類(lèi)脂肪等的黃色物質(zhì),，多由脂肪代謝紊亂、神經(jīng)血管功能失調(diào)引起,。常導(dǎo)致血栓形成,、供血障礙等。動(dòng)脈粥樣硬化一直是西方發(fā)達(dá)國(guó)家的主要死亡原因,。近年來(lái)隨著中國(guó)人民生活水平的提高和飲食習(xí)慣的改變,，該病也成為了中國(guó)的主要死亡原因。
過(guò)去的研究證實(shí)IL-5可通過(guò)阻斷巨噬細(xì)胞攝取氧化型低密度脂蛋白（oxidized low density lipoprotein,，ox-LDL）來(lái)生成T15/EO6 IgM抗體,，巨噬細(xì)胞IL-5表達(dá)缺陷可加速動(dòng)脈粥樣硬化形成。此外,，肝X受體(liver X receptors,，LXRs)作為一類(lèi)配體激活轉(zhuǎn)錄因子，可以誘導(dǎo)巨噬細(xì)胞ABCA1表達(dá)和膽固醇外流,，從而抑制動(dòng)脈粥樣硬化形成,。然而，目前并不清楚巨噬細(xì)胞IL-5表達(dá)調(diào)控是否與LXR的抗動(dòng)脈硬化特性具有相關(guān)性,。
在這篇新文章中,，研究人員初步確定了LXR配體(T0901317)可誘導(dǎo)巨噬細(xì)胞IL-5蛋白表達(dá)和分泌,。LXR過(guò)表達(dá)則IL-5蛋白表達(dá)增高,，反之IL-5蛋白表達(dá)則受到抑制。此外,，研究人員發(fā)現(xiàn)LXR激活提高了啟動(dòng)子活性,，增進(jìn)了IL-5轉(zhuǎn)錄，促進(jìn)了LXR?LXR效應(yīng)元件復(fù)合物形成,，并維持了IL-5蛋白的穩(wěn)定性,。在體內(nèi)，他們發(fā)現(xiàn)T0901317提高了野生型小鼠血漿中的IL-5和總體IgM水平,，以及多個(gè)組織中的IL-5表達(dá),。在LDL受體敲除(LDLR-/-)的小鼠中，T0901317提高了主動(dòng)脈根部區(qū)域的IL-5表達(dá),。
這些研究結(jié)果表明巨噬細(xì)胞IL-5是LXR激活的一個(gè)靶基因,，誘導(dǎo)巨噬細(xì)胞IL-5表達(dá)有可能與LXR抑制動(dòng)脈粥樣硬化相關(guān)。(生物谷Bioon.com)
doi: 10.1074/jbc.M112.403394
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Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression
Yuanli Chen‡§, Yajun Duan‡§,1,2, Yanhua Kang‡§, Xiaoxiao Yang‡§, Meixiu Jiang‡§, Ling Zhang‡§, Guangliang Li‡§, Zhinan Yin‡§, Wenquan Hu‡§, Pengzhi Dong‡§, Xiaoju Li‡§, David P. Hajjar¶ and Jihong Han‡§,1,3
IL-5 stimulates production of T15/EO6 IgM antibodies that can block the uptake of oxidized low density lipoprotein by macrophages, whereas a deficiency in macrophage IL-5 expression accelerates development of atherosclerosis. Liver X receptors (LXRs) are ligand-activated transcription factors that can induce macrophage ABCA1 expression and cholesterol efflux, thereby inhibiting the development of atherosclerosis. However, it remains unknown whether additional mechanisms, such as the regulation of macrophage IL-5 expression, are related to the anti-atherogenic properties of LXR. We initially defined IL-5 expression in macrophages where the LXR ligand (T0901317) induced macrophage IL-5 protein expression and secretion. The overexpression of LXR increased, whereas its knockdown inhibited IL-5 expression. Furthermore, we found that LXR activation increased IL-5 transcripts, promoter activity, formation of an LXR·LXR-responsive element complex, and IL-5 protein stability. In vivo, we found that T0901317 increased IL-5 and total IgM levels in plasma and IL-5 expression in multiple tissues in wild type mice. In LDL receptor knock-out (LDLR−/−) mice, T0901317 increased IL-5 expression in the aortic root area. Taken together, our studies demonstrate that macrophage IL-5 is a target gene for LXR activation, and the induction of macrophage IL-5 expression can be related to LXR-inhibited atherosclerosis.
