IL-11與重癥急性胰腺炎

房小龍 薛育政

·綜述·

IL-11與重癥急性胰腺炎

房小龍 薛育政

重癥急性胰腺炎(SAP)病死率高、并發(fā)癥多。近年來關(guān)于促炎癥因子在其發(fā)病機(jī)制中的作用成為研究熱點(diǎn)[1-6]，因此利用抗炎癥因子治療SAP日益受到重視。IL-11(interleukin-11,IL-11)是近來報(bào)道的一種有效的抗炎癥因子[7]，它在腸道炎癥、內(nèi)毒素血癥及輻射導(dǎo)致胸部損傷的動(dòng)物模型中具有保護(hù)性作用。本文僅就目前IL-11在SAP治療中的應(yīng)用進(jìn)展作一綜述。

一、IL-11的結(jié)構(gòu)及生物學(xué)作用

IL-11主要來源于間質(zhì)細(xì)胞[8]，它通過與特異性受體(IL-11R)結(jié)合而起作用。IL-11由α鏈和信號(hào)轉(zhuǎn)導(dǎo)亞單位gp130所組成。后者為IL-6R、LIFR、OSMR、CNTFR所共有。報(bào)道顯示，小鼠、非人靈長類和人類的IL-11氨基酸序列物同源性達(dá)90%以上。人IL-11基因位于第19號(hào)染色體上，由5個(gè)外顯子和4個(gè)內(nèi)含子組成，全長為7000 bp，含1500 bp和2500 bp的兩個(gè)RNA轉(zhuǎn)錄體。人IL-11 cDNA編碼由199個(gè)氨基酸組成的前肽，分子質(zhì)量為192 000，其中含21個(gè)氨基酸殘基組成的疏水性信號(hào)序列。IL-11多肽結(jié)構(gòu)中無半胱氨酸殘基或潛在糖基化位點(diǎn)，亦無二硫鍵結(jié)構(gòu)和高度螺旋化結(jié)構(gòu)。IL-11是具有多種功能的細(xì)胞因子,它能刺激巨核系列細(xì)胞生長，刺激骨髓巨核細(xì)胞復(fù)制，提高外周血小板數(shù)量[9]；調(diào)節(jié)巨噬細(xì)胞前體細(xì)胞的增殖及分化[10]；通過依賴T-淋巴細(xì)胞機(jī)制刺激B細(xì)胞免疫球蛋白的產(chǎn)生[11]。近來研究表明，IL-11對因放化療[12]及局限性腸道缺血病[13]引起的腸黏膜損傷具有預(yù)防性保護(hù)作用。此外，臨床試驗(yàn)表明，IL-11也可引起血漿中急性炎癥反應(yīng)物濃度增加，包括C反應(yīng)蛋白、纖維蛋白原和結(jié)合珠蛋白等。應(yīng)用IL-11治療能減輕輻射引起的胸部損傷嚴(yán)重度[13]及降低內(nèi)毒素血癥的病死率[14-15]。這些研究發(fā)現(xiàn)均表明IL-11起著抗炎癥因子的作用。

二、IL-11治療SAP的作用機(jī)制

1．阻滯TNF-α mRNA表達(dá)及降低血清TNF-α mRNA水平：Shimizu等[16]應(yīng)用重組人類白介素-11(recombinant human interleukin-11,rhIL-11)治療蛙皮素聯(lián)合脂多糖誘導(dǎo)的小鼠急性壞死性胰腺炎(acute necrotizing pancreatitis, ANP)。結(jié)果顯示ANP 小鼠的血清淀粉酶、脂肪酶及TNF-α水平顯著升高，胰腺組織內(nèi)出現(xiàn)水腫、炎癥細(xì)胞浸潤及胰腺出血、壞死等病變。應(yīng)用rhIL-11預(yù)處理后，ANP小鼠制模后6～8 h內(nèi)的血清淀粉酶、脂肪酶水平及血清TNF-α濃度顯著降低。在胰腺炎誘導(dǎo)后6 h給予rIL-11治療，胰腺的損傷程度也明顯改善。

他們認(rèn)為，IL-11通過阻滯TNF-α mRNA的表達(dá)，降低血清TNF-α水平而減輕ANP小鼠胰腺的損傷程度。TNF-α在炎癥早期為高表達(dá)的促炎癥因子，其介導(dǎo)組織損傷的機(jī)制是通過激活炎癥細(xì)胞[17]、上調(diào)黏附分子的表達(dá)[18]及促進(jìn)一氧化氮和氧自由基的產(chǎn)生[19-20]。有動(dòng)物實(shí)驗(yàn)提示[21],給予TNF-α拮抗劑可減輕實(shí)驗(yàn)性ANP動(dòng)物的胰腺壞死程度，改善生化指標(biāo)，提高生存率。

2．抑制巨噬細(xì)胞內(nèi)NF-κB的轉(zhuǎn)錄活性，阻斷其介導(dǎo)的級(jí)聯(lián)反應(yīng)：NF-κB是體內(nèi)一種具有多相轉(zhuǎn)錄調(diào)節(jié)作用的蛋白質(zhì)，它對于激活體內(nèi)許多炎癥因子具有重要作用[22]。NF-κB廣泛存在于機(jī)體各種細(xì)胞胞質(zhì)中，是許多促炎細(xì)胞因子、炎癥介質(zhì)、黏附分子和急性期反應(yīng)蛋白所必須的轉(zhuǎn)錄因子。NF-κB的活化能引起一系列基因表達(dá)的增加，包括TNF-α、IL-1、IL-6等細(xì)胞因子、細(xì)胞間黏附分子-1(ICAM-1)及P-選擇素、E-選擇素等，進(jìn)而參與機(jī)體的炎癥反應(yīng)和免疫反應(yīng)。由NF-κB調(diào)節(jié)的產(chǎn)物如TNF-α、IL-1β又能激活NF-κB，從而形成了一個(gè)級(jí)聯(lián)放大反應(yīng)。Trepicchio等[23]在研究IL-11調(diào)節(jié)巨噬細(xì)胞功能時(shí)，發(fā)現(xiàn)內(nèi)毒素通過激活巨噬細(xì)胞內(nèi)的NF-κB活性,促進(jìn)IL-6、TNF等基因的轉(zhuǎn)錄，而用rhIL-11治療后能明顯抑制巨噬細(xì)胞內(nèi)NF-κB的轉(zhuǎn)錄活性，阻滯了NF-κB活化誘導(dǎo)炎癥介質(zhì)的產(chǎn)生，減緩炎癥的發(fā)展。

3．抑制NO的產(chǎn)生，改善胰腺微循環(huán)：Trepicchio等[7]在成功誘導(dǎo)小鼠內(nèi)毒素血癥模型后，用rhIL-11預(yù)處理能夠阻滯脂多糖引起的TNF-α、IL-1β、IFN-γ等水平的升高，但對IL-12、p40、IL-6及IL-10水平?jīng)]有影響。因此，他們認(rèn)為，rhIL-11消弱炎癥反應(yīng)的機(jī)制是通過下調(diào)促炎癥因子TNF-α、IL-1β、IFN-γ的釋放，同時(shí)抑制一氧化氮(NO)的產(chǎn)生。由于NO在SAP發(fā)病機(jī)制中具有重要作用，因此IL-11通過抑制NO的產(chǎn)生，使NO處于低水平，從而舒張血管平滑肌，降低外周阻力，對胰腺微循環(huán)的改善具有保護(hù)作用，降低了SAP的損傷程度。

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2008-05-09)

(本文編輯：屠振興)

10.3760/cma.j.issn.1674-1935.2009.06.026

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