馮鵬輝， 單風(fēng)平

(中國(guó)醫(yī)科大學(xué) 基礎(chǔ)醫(yī)學(xué)院 免疫學(xué)教研室，遼寧 沈陽(yáng) 110122)

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生物活性肽
——蛋氨酸腦啡肽的免疫調(diào)節(jié)作用及其應(yīng)用前景

馮鵬輝， 單風(fēng)平*

(中國(guó)醫(yī)科大學(xué) 基礎(chǔ)醫(yī)學(xué)院 免疫學(xué)教研室，遼寧 沈陽(yáng) 110122)

源自腎上腺前腦啡肽原的具有嗎啡樣生物活性的內(nèi)源性神經(jīng)肽蛋氨酸腦啡肽(methionine enkephalin，MENK)，由5個(gè)氨基酸殘基Tyr-Gly-Gly-Phe-Met組成，與G蛋白偶聯(lián)的7次跨膜特異性受體結(jié)合后發(fā)揮不同的生物學(xué)功能。目前，對(duì)蛋氨酸腦啡肽的作用及其機(jī)制研究已經(jīng)取得了很大進(jìn)展。本文就MENK對(duì)于免疫系統(tǒng)的調(diào)節(jié)及其對(duì)腫瘤、自身免疫病、艾滋病等免疫系統(tǒng)相關(guān)疾病的治療作用予以綜述。

蛋氨酸腦啡肽；阿片生長(zhǎng)因子；阿片肽；阿片生長(zhǎng)因子受體；免疫調(diào)節(jié)

由5個(gè)氨基酸殘基組成的阿片樣物質(zhì)腦啡肽系前腦啡肽原加工修飾而成[1]。根據(jù)第5個(gè)氨基酸殘基的組成不同可分為亮氨酸腦啡肽和蛋氨酸腦啡肽。MENK也被稱作內(nèi)源性神經(jīng)肽，參與免疫和神經(jīng)內(nèi)分泌系統(tǒng)的調(diào)節(jié)環(huán)，作為信使參與固有免疫和適應(yīng)性免疫調(diào)節(jié)[2]。前腦啡肽原A基因編碼的蛋氨酸腦啡肽，具有雙向調(diào)控的作用，廣泛地存在于神經(jīng)組織與非神經(jīng)組織。在適宜濃度范圍時(shí)，MENK作為緊張性激活劑而參與免疫調(diào)節(jié)和細(xì)胞增殖[3]。通過自分泌與旁分泌與巨噬細(xì)胞、NK細(xì)胞、LAK細(xì)胞、淋巴細(xì)胞等免疫系統(tǒng)相關(guān)細(xì)胞表面阿片受體結(jié)合后，參與cAMP-PKA、蛋白激酶、Ca2+-鈣調(diào)蛋白、PKC等信號(hào)調(diào)節(jié)通路后對(duì)免疫系統(tǒng)起到調(diào)節(jié)作用。

1 MENK受體的分類與生物學(xué)功能

阿片肽具有生長(zhǎng)調(diào)節(jié)功能，故稱之為阿片生長(zhǎng)因子(opioid growth factor,OGF)，除此之外，早期對(duì)腦啡肽的研究集中于其鎮(zhèn)痛活性，之后Plotnikoff等[4]、Nagy等[5]首先發(fā)現(xiàn)小鼠體內(nèi)給予腦啡肽后能顯著減少其足休克誘導(dǎo)的神經(jīng)相關(guān)癥狀，同時(shí)一定程度上減少聽源性癲癇的發(fā)作，不久還證實(shí)MENK通過激活脂氧化酶途徑誘導(dǎo)人分葉核白細(xì)胞呼吸爆發(fā)進(jìn)而增強(qiáng)其細(xì)胞內(nèi)殺傷活性。Maslov等[6]發(fā)現(xiàn)鼠對(duì)于持續(xù)性等張性缺氧的長(zhǎng)期適應(yīng)，顯著增強(qiáng)了心肌對(duì)不可逆的急性缺血——再灌注損傷的耐受能力，梗死面積限制性作用由阿片肽激活外周的δ2、μ受體所致。經(jīng)典的阿片受體包括δ、μ、κ受體(DOR、MOR、KOR)等幾種亞型。阿片肽還可以與后來新發(fā)現(xiàn)的在序列上不與經(jīng)典阿片受體具有同源性的阿片生長(zhǎng)因子受體(opioid growth factor receptor,OGFr)結(jié)合。直接作用于免疫系統(tǒng)的有δ、κ受體，而μ、δ受體在神經(jīng)內(nèi)分泌調(diào)節(jié)中發(fā)揮著重要作用。阿片生長(zhǎng)因子受體定位于核膜外層，在核轉(zhuǎn)運(yùn)蛋白β和Ran的引導(dǎo)下OGF與OGFr結(jié)合后形成OGF-OGFr復(fù)合體，在OGFr上的核定位序列的作用下進(jìn)行核質(zhì)轉(zhuǎn)運(yùn)，進(jìn)而進(jìn)一步發(fā)揮其特定的生物學(xué)功能[7-8]。

2 MENK的免疫調(diào)節(jié)作用

2.1 對(duì)巨噬細(xì)胞的作用

巨噬細(xì)胞屬于專職抗原提呈細(xì)胞(antigen-presenting cell，APC)，可表達(dá)多種膜型分子和分泌型分子，如Toll樣受體(Toll-like receptor，TLR)、IFN-γ、MCP-1受體等。巨噬細(xì)胞具有抗原提呈、細(xì)胞毒性作用、細(xì)胞碎片清除、調(diào)節(jié)炎癥反應(yīng)維持穩(wěn)態(tài)等生理功能，在固有免疫和適應(yīng)性免疫應(yīng)答等方面起著重要作用，通過自分泌與旁分泌的方式而使MENK作為調(diào)節(jié)分子調(diào)節(jié)巨噬細(xì)胞，如吞噬作用、表型極化[9-10]。巨噬細(xì)胞具有2種極化表型，即經(jīng)典活化的巨噬細(xì)胞M1和替代性活化的巨噬細(xì)胞M2[11]。M1能產(chǎn)生促炎癥分子如TNF-α，并能高效清除病原微生物和腫瘤細(xì)胞。M2主要產(chǎn)生抗炎癥分子，例如IL-10中和炎癥反應(yīng)，促進(jìn)血管生成以及重塑受損組織。Chen等[12]在研究中發(fā)現(xiàn)，MENK能有效地誘導(dǎo)M2巨噬細(xì)胞極化為M1型巨噬細(xì)胞，繼而調(diào)節(jié)宿主免疫系統(tǒng)TH1細(xì)胞免疫應(yīng)答；體內(nèi)實(shí)驗(yàn)表明MENK能下調(diào)巨噬細(xì)胞CD206及精氨酸酶-1(M2標(biāo)志物)。同時(shí)，它能上調(diào)CD64、MHC-II及NO合酶(M1標(biāo)志物)，體外實(shí)驗(yàn)表明，在10-12mol/L時(shí)MENK能顯著上調(diào)BMDMs細(xì)胞中ROS與iNOS的水平，從而促進(jìn)巨噬細(xì)胞介導(dǎo)的細(xì)胞毒性作用。

2.2 對(duì)T淋巴細(xì)胞的作用

T淋巴細(xì)胞由淋巴樣前體分化而來，在胸腺內(nèi)先后歷經(jīng)陽(yáng)性選擇和陰性選擇后進(jìn)一步發(fā)育成熟，分化為CD3+CD4+或CD3+CD8+細(xì)胞表型的TCRαβT細(xì)胞，也有少部分分化為γδT細(xì)胞。Li等[13]通過體內(nèi)體外實(shí)驗(yàn)研究發(fā)現(xiàn)，MENK能上調(diào)CD8+T細(xì)胞百分比，MENK與表達(dá)增多的OGFr結(jié)合后在CTL活化中起到關(guān)鍵作用。MENK誘導(dǎo)的T細(xì)胞信號(hào)與Ca2+內(nèi)流入胞質(zhì)以及T細(xì)胞活化核內(nèi)因子的上調(diào)有關(guān)，這種作用可被MENK的拮抗劑納曲酮抑制。Shan等[14]發(fā)現(xiàn)當(dāng)MENK單獨(dú)使用、MENK與IL-2或MENK與IFN-γ聯(lián)用時(shí)，通過直接或間接途徑促使其他免疫細(xì)胞如巨噬細(xì)胞、DCs分泌IL-12。MENK能誘導(dǎo)CD8+T細(xì)胞的細(xì)胞毒作用，能顯著表達(dá)CTL最重要的標(biāo)志物CD28。同時(shí)FasL(CD178)和Prf一致性地高表達(dá)[15]。

2.3 對(duì)B淋巴細(xì)胞的作用

B細(xì)胞在骨髓內(nèi)發(fā)育歷經(jīng)從淋巴樣前體細(xì)胞到未成熟的B細(xì)胞，之后遷移到外周免疫器官與組織如淋巴結(jié)、脾發(fā)育成熟至細(xì)胞表面出現(xiàn)完整的IgM、IgD分子。分為B1和B2兩大細(xì)胞亞群，具有分泌抗體、提呈抗原和免疫調(diào)節(jié)等功能。Gabrilovac等[16]在對(duì)雌性和雄性鼠分別予以MENK后發(fā)現(xiàn)，雄性鼠用2.5 和5 mg/kg的劑量處理后，LPS刺激的脾源性B淋巴細(xì)胞的增值能力增強(qiáng)，但在雌鼠中作用相反；同時(shí)若在注射MENK之前注射納曲酮10 mg/kg后，該增殖作用會(huì)被可逆性抑制。Zagon等[17]利用阿片肽拮抗劑、反義技術(shù),SiRNA技術(shù)以及OGF中和抗體發(fā)現(xiàn)，MENK孵育72 h后，OGF-OGFr軸呈劑量依賴性通過P16或P21周期蛋白依賴性抑制途徑抑制細(xì)胞數(shù)量，對(duì)LPS刺激的脾源性B細(xì)胞的生長(zhǎng)抑制率達(dá)到43%。

2.4 對(duì)樹突狀細(xì)胞的作用

樹突狀細(xì)胞(dendritic cell，DC)是專職抗原提呈細(xì)胞，是唯一具體誘導(dǎo)初始T細(xì)胞活動(dòng)的APC，成熟DC細(xì)胞中MHC分子、B7(CD80/CD86)高表達(dá)，但不像未成熟DC細(xì)胞具有吞噬抗原的能力。Meng等[18]發(fā)現(xiàn)MENK具有雙向調(diào)節(jié)的作用，在生理濃度為10-11或10-15mol/L時(shí)能促進(jìn)DC細(xì)胞增殖，當(dāng)濃度高達(dá)10-6或低于10-18mol/L時(shí)會(huì)延遲樹突狀細(xì)胞的生長(zhǎng)，可能是MENK與OGFr結(jié)合后上調(diào)周期蛋白依賴性激酶抑制劑而推遲G/S期。研究表明在MENK作用下，負(fù)載RG(Rac-1抗原)的骨髓源性樹突狀細(xì)胞(bone marrow-derived dendritic cells,BMDCs)在功能與表型上更加成熟，通過FCM實(shí)驗(yàn)發(fā)現(xiàn)MENK能夠顯著增加負(fù)載RG的BMDCs細(xì)胞表達(dá)CD86、CD83和CD40，進(jìn)一步實(shí)驗(yàn)后，SEM和FCM表明BMDCs細(xì)胞成熟后顯出更多突起，具有更強(qiáng)的吞噬能力；ELISA實(shí)驗(yàn)證明MENK負(fù)載RG能增加IL-12p40和IL-12p70的分泌，減少TNF-α的分泌[15]。體內(nèi)外實(shí)驗(yàn)[19-20]，表明MENK可以誘導(dǎo)DCs主要極化為髓樣樹突狀細(xì)胞mDC亞型，而不是漿樣樹突狀細(xì)胞pDC，這有利于TH1細(xì)胞介導(dǎo)的免疫反應(yīng)，RT-PCR實(shí)驗(yàn)顯示MENK能夠增加骨髓源性樹突狀細(xì)胞δ、κ受體的表達(dá)，分泌更高水平的促炎細(xì)胞因子IL-12P70、TNF-α。

2.5 對(duì)NK細(xì)胞的作用

NK具有直接殺傷靶細(xì)胞的作用，能夠通過釋放含穿孔素蛋白和顆粒酶的顆粒或FasL誘導(dǎo)凋亡的非特異性殺傷，還可以通過抗體依賴性細(xì)胞介導(dǎo)的細(xì)胞毒作用(antibody dependent cell-mediated cytotoxicity，ADCC)，利用細(xì)胞表面的IgG Fc受體來識(shí)別與抗體特異性結(jié)合的靶細(xì)胞。MENK在適宜濃度時(shí)能激活NK細(xì)胞，上調(diào)免疫系統(tǒng)[21-23]。Hua等[24]發(fā)現(xiàn)在10-12mol/L時(shí)，與RPMI 1640 培養(yǎng)基對(duì)照組相比，MENK實(shí)驗(yàn)組的NK細(xì)胞陽(yáng)性率達(dá)到(7.47±0.35)%，高于對(duì)照組(4.98±0.59)%(P<0.01)。Wang等[25]在研究癌癥患者免疫細(xì)胞時(shí)，通過FCM檢測(cè)NK細(xì)胞(CD16+、CD56+)表面標(biāo)志物發(fā)現(xiàn)癌癥患者體內(nèi)NK細(xì)胞用MENK治療后由(6.98±1.59)%增加到(25.39±4.42)%。

3 對(duì)免疫相關(guān)疾病的作用

3.1 抗腫瘤

自20世紀(jì)90年代以來，大量研究致力于發(fā)現(xiàn)MENK對(duì)腫瘤細(xì)胞生長(zhǎng)的調(diào)節(jié)作用。對(duì)腫瘤患者與荷瘤鼠予以MENK治療一段時(shí)間后，腫瘤發(fā)生率有所降低，腫瘤周期延長(zhǎng)，同時(shí)能延長(zhǎng)施藥對(duì)象的生存期[13,26]。研究數(shù)據(jù)表明[27-29]，某些癌癥細(xì)胞核膜上的ζ受體與MENK結(jié)合后，在體外能顯著抑制腫瘤細(xì)胞生長(zhǎng)?；贛ENK對(duì)免疫細(xì)胞的調(diào)節(jié)恢復(fù)作用，對(duì)于因放療化療免疫系統(tǒng)受損的癌癥患者而言，MENK將有望作為治療物幫助恢復(fù)紊亂的免疫系統(tǒng)，同時(shí)在化療時(shí)亦可以起到輔助，減少其副作用。OGF-OGFr軸能通過延遲細(xì)胞周期G1/S期來緊張性地調(diào)節(jié)細(xì)胞增殖。對(duì)胰腺癌的研究[27,30-31]中發(fā)現(xiàn)，OGF亦可直接通過增加P21周期蛋白依賴抑制性激酶或減少細(xì)胞周期依賴性激酶CDK-2的作用方式抑制DNA合成和胰腺癌細(xì)胞增殖。Donahue等[32]在對(duì)婦科致死率最高的惡性腫瘤卵巢癌進(jìn)行研究時(shí)發(fā)現(xiàn)，對(duì)荷瘤鼠施以MENK或低劑量納曲酮后，與對(duì)照組相比腫瘤結(jié)節(jié)數(shù)量分別減少42%和39%，腫瘤累積重量分別減少69%和46%。由數(shù)據(jù)可以看出，OGF能在很大程度上抑制腫瘤的發(fā)生與發(fā)展。該作用機(jī)制在于其能抑制瘤體血管生成及細(xì)胞增殖[33-35]。肝母細(xì)胞瘤是2歲兒童以下最常見的、惡性程度高的肝臟腫瘤。對(duì)其最近研究中發(fā)現(xiàn)，兒科肝母細(xì)胞瘤患者盡管通過手術(shù)聯(lián)合化療后能顯著提高生存率，但傳統(tǒng)化療藥物的毒性誘導(dǎo)中性粒細(xì)胞減少癥，大大增加嚴(yán)重的全身性感染的幾率及其并發(fā)癥，而應(yīng)用MENK在抑制腫瘤細(xì)胞生長(zhǎng)的同時(shí)不會(huì)引起類似副反應(yīng)[36]。McLaughlin等[37]在對(duì)甲狀腺濾泡細(xì)胞源性癌的研究時(shí)，利用免疫組化、siRNA介導(dǎo)的基因敲低等技術(shù)發(fā)現(xiàn)，OGF-OGFr軸也存在于甲狀腺未分化癌ATC細(xì)胞中，可逆性地以受體介導(dǎo)的劑量依賴性方式，在10-6mol/L時(shí)96 h的周期內(nèi)OGF對(duì)腫瘤細(xì)胞復(fù)制抑制率達(dá)到13%～30%，這意味著MENK將可能作為生物治療制劑用于該類癌癥的臨床治療。

3.2 抗自身免疫病

用MOG(髓鞘少突膠質(zhì)細(xì)胞糖蛋白)+OGF處理C57BL/6小鼠后與只用MOG刺激的對(duì)照組相比，超過60%沒有表現(xiàn)出EAE(實(shí)驗(yàn)性自身免疫性腦脊髓炎)病癥，而對(duì)照組全部發(fā)病，實(shí)驗(yàn)進(jìn)行至第30天，60% MOG+OGF給藥小鼠癥狀緩解而對(duì)照組只有4%，給藥OGF的小鼠活化的星形膠質(zhì)細(xì)胞與受損的神經(jīng)元數(shù)量相對(duì)減少，且不表現(xiàn)出要髓核脫髓鞘的癥狀[38]。該實(shí)驗(yàn)結(jié)果可指導(dǎo)用于臨床治療自身免疫病多發(fā)性硬化癥。OGF-OGFr軸通過上調(diào)細(xì)胞周期依賴性抑制性激酶途徑，特別是P16與P21，以緊張性激活的方式抑制用PHA植物血凝素刺激的T細(xì)胞增殖，嚴(yán)格地維持著細(xì)胞更新與恢復(fù)機(jī)制，起到免疫抑制劑的作用，從而抑制小鼠MOG誘導(dǎo)的實(shí)驗(yàn)性自身免疫性腦脊髓炎，進(jìn)而調(diào)節(jié)自身免疫病[7,30,39-40]。

3.3 抗艾滋病

獲得性免疫缺陷綜合征(Acquired Immune Deficiency Syndrome,AIDS)是由HIV逆轉(zhuǎn)錄病毒引起。通過CD4分子、趨化因子受體等介導(dǎo)感染，免疫細(xì)胞和非免疫細(xì)胞均有易感性。刺激OGFr可抑制淋巴細(xì)胞中該病毒的增殖[41-42]。利用流式細(xì)胞技術(shù)、Western Blotting等檢測(cè)細(xì)胞周期、絲裂原活化的蛋白激酶(MAPK)等發(fā)現(xiàn)，對(duì)CEM×174 細(xì)胞施以1 μmol/L的MENK后，猴免疫缺陷病毒感染的細(xì)胞生存率顯著增加，凋亡的細(xì)胞相應(yīng)減少，可能是通過Ca2+-PKC-MAPK級(jí)聯(lián)作用在病毒早期感染發(fā)揮作用[43]。

3.4 抗炎癥作用

炎癥是機(jī)體對(duì)損傷因子產(chǎn)生的防御性的反應(yīng)，是一種損傷與抗損傷的統(tǒng)一表現(xiàn)。MENK通過調(diào)節(jié)促炎癥和抗炎癥細(xì)胞因子來調(diào)節(jié)炎癥反應(yīng)[44]。白細(xì)胞分泌的MENK在炎癥反應(yīng)中起到鎮(zhèn)痛和免疫調(diào)節(jié)的重要作用[45]。Owczarek等[46]通過對(duì)43例潰瘍性結(jié)腸炎及38例克羅恩氏病患者腸炎病灶切片后發(fā)現(xiàn)，MENK的含量明顯高于非炎癥部位。Spetea等[47]利用放射性免疫分析法和受體結(jié)合分析后發(fā)現(xiàn)，關(guān)節(jié)炎接種鼠4周后，紋狀體、額皮質(zhì)和枕皮質(zhì)組織MENK含量增加，最為明顯的是腰部脊髓中MENK增加達(dá)到232%。以上發(fā)現(xiàn)均表明MENK在炎癥反應(yīng)與抗炎癥反應(yīng)的平衡調(diào)節(jié)中發(fā)揮著重要的作用。

4 展 望

對(duì)蛋氨酸腦啡肽的生物調(diào)節(jié)作用研究日趨完善，對(duì)其鎮(zhèn)痛、免疫調(diào)節(jié)的功能在臨床上已得到廣泛應(yīng)用。目前，國(guó)內(nèi)外對(duì)蛋氨酸腦啡肽在腫瘤治療方面取得了顯著進(jìn)展，特別是其通過阿片受體進(jìn)行調(diào)節(jié)更是有著獨(dú)特之處。作為抗腫瘤新藥，在國(guó)外已經(jīng)進(jìn)入臨床三期試驗(yàn)階段，國(guó)內(nèi)亦有大量的投資與研究。其可作為新的免疫調(diào)節(jié)劑，發(fā)揮其廣譜抗腫瘤效用。但是，對(duì)于某些腫瘤如人頭頸鱗狀細(xì)胞癌中OGFr的低表達(dá)是否涉及到腫瘤細(xì)胞逃避內(nèi)源性MENK的抑制作用到目前還沒有系統(tǒng)的研究。此外，以往的研究?jī)?nèi)容更多地集中在細(xì)胞和個(gè)體層面來對(duì)腦啡肽生物學(xué)功能進(jìn)行發(fā)掘，后期需要更加深入的研究，從分子水平來揭示其信號(hào)通路與其生理功能的作用機(jī)制，從而進(jìn)一步開發(fā)其功能，MENK的應(yīng)用也必將有著更為廣闊的前景。

[1] Marcotte I, Dufourc E J, Ouellet M, et al. Interaction of the neuropeptide met-enkephalin with zwitterionic and negatively charged bicelles as viewed by 31P and 2H solid-state NMRl [J].Biophys J, 2003，85(1):328-339.

[2] Piva M, Moreno J I, Jenkins F S, et al. In vitro modulation of cytokine expression by enkephalin-derived peptidesl[J].Neuroimmunomodulation, 2005，12(6):339-347.

[3] Zagon I S, Verderame M F, McLaughlin P J. The biology of the opioid growth factor receptor (OGFr)l[J].Brain Res Brain Res Rev, 2002，38(3):351-376.

[4] Plotnikoff N P, Kastin A J, Coy D H, et al. Neuropharmacological actions of enkephalin after systemic administrationl[J].Life Sci, 1976，19(8):1283-1288.

[5] Nagy J T, Foris G, Fulop T, et al. Activation of the lipoxygenase pathway in the methionine enkephalin induced respiratory burst in human polymorphonuclear leukocytesl[J].Life Sci, 1988，42(22):2299-2306.

[6] Maslov L N, Naryzhnaia N V, Tsibulnikov S Y, et al. Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxial[J].Life Sci, 2013，93(9-11):373-379.

[7] Cheng F, McLaughlin P J, Verderame M F, et al. The OGF-OGFr axis utilizes the p16INK4a and p21WAF1/CIP1 pathways to restrict normal cell proliferationl[J].Mol Biol Cell, 2009，20(1):319-327.

[8] Zagon I S, McLaughlin P J. Opioids and differentiation in human cancer cellsl[J].Neuropeptides, 2005，39(5):495-505.

[9] Valdes-Tovar M, Escobar C, Solis-Chagoyan H, et al. Constant light suppresses production of Met-enkephalin-containing peptides in cultured splenic macrophages and impairs primary immune response in ratsl[J].Chronobiol Int, 2015，32(2):164-177.

[10]Naito M. Macrophage differentiation and function in health and diseasel[J].Pathol Int, 2008，58(3):143-155.

[11]Mantovani A,Sica A,Locati M. Macrophage polarization comes of agel[J].Immunity, 2005，23(4):344-346.

[12]Chen W, Liu J, Meng J, et al. Macrophage polarization induced by neuropeptide methionine enkephalin (MENK) promotes tumoricidal responsesl[J].Cancer Immunol Immunother, 2012，61(10):1755-1768.

[13]Li W, Chen W, Herberman R B, et al. Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)l[J].Cancer Lett, 2014，344(2):212-222.

[14]Shan F, Xia Y, Wang N, et al. Functional modulation of the pathway between dendritic cells (DCs) and CD4+T cells by the neuropeptide: methionine enkephalin (MENK)l[J].Peptides, 2011，32(5):929-937.

[15]Li W, Meng J, Li X, et al. Methionine enkephalin (MENK) improved the functions of bone marrow-derived dendritic cells (BMDCs) loaded with antigenl[J].Hum Vaccin Immunother, 2012，8(9):1236-1242.

[16]Gabrilovac J, Marotti T. Gender-related differences in murine T-and B-lymphocyte proliferative ability in response to in vivo [Met(5)]enkephalin administrationl[J].Eur J Pharmacol, 2000，392(1-2):101-108.

[17]Zagon I S, Donahue R N, Bonneau R H, et al. B lymphocyte proliferation is suppressed by the opioid growth factor-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseasesl[J].Immunobiology, 2011，216(1-2):173-183.

[18]Meng Y, Wang Q, Zhang Z, et al. Synergistic effect of methionine encephalin (MENK) combined with pidotimod(PTD) on the maturation of murine dendritic cells (DCs)l[J].Hum Vaccin Immunother, 2013，9(4):773-783.

[19]Liu J, Chen W, Meng J, et al. Induction on differentiation and modulation of bone marrow progenitor of dendritic cell by methionine enkephalin (MENK)l[J].Cancer Immunol Immunother, 2012，61(10):1699-1711.

[20]Ardavin C, Martinez del Hoyo G, Martin P, et al. Origin and differentiation of dendritic cellsl[J].Trends In Immunology, 2001，22(12):691-700.

[21]McLaughlin P J, Zagon I S. The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and diseasel[J].Biochem Pharmacol, 2012，84(6):746-755.

[22]Byun S W, Chang Y J, Chung I S, et al. Helicobacter pylori decreases p27 expression through the delta opioid receptor-mediated inhibition of histone acetylation within the p27 promoterl[J].Cancer Lett, 2012，326(1):96-104.

[23]Ghaffari K, Savadkuhi S T, Honar H, et al. Obstructive cholestasis alters intestinal transit in mice: role of opioid systeml[J].Life Sci, 2004，76(4):397-406.

[24]Hua H, Lu C, Li W, et al. Comparison of stimulating effect on subpopulations of lymphocytes in human peripheral blood by methionine enkephalin with IL-2 and IFN-gammal[J].Hum Vaccin Immunother, 2012，8(8):1082-1089.

[25]Wang Q, Gao X, Yuan Z, et al. Methionine enkephalin (MENK) improves lymphocyte subpopulations in human peripheral blood of 50 cancer patients by inhibiting regulatory T cells (Tregs)l[J].Hum Vaccin Immunother, 2014，10(7):1836-1840.

[26]Zagon I S, Jaglowski J R, Verderame M F, et al. Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinomal[J].Cancer Chemother Pharmacol, 2005，56(5):510-520.

[27]Smith J P, Bingaman S I, Mauger D T, et al. Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancerl[J].Open Access J Clin Trials, 2010，2010(2):37-48.

[28]Donahue R N, McLaughlin P J, Zagon I S. Cell proliferation of human ovarian cancer is regulated by the opioid growth factor-opioid growth factor receptor axisl[J].Am J Physiol Regul Integr Comp Physiol, 2009，296(6):1716-1725.

[29]Zagon I S, Kreiner S, Heslop J J, et al. Prevention and delay in progression of human pancreatic cancer by stable overexpression of the opioid growth factor receptorl[J].Int J Oncol, 2008，33(2):317-323.

[30]Cheng F, McLaughlin P J, Verderame M F, et al. The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancerl[J].Mol Cancer, 2008，7:5.

[31]Zagon I S, Roesener C D, Verderame M F, et al. Opioid growth factor regulates the cell cycle of human neoplasiasl[J].Int J Oncol, 2000，17(5):1053-1061.

[32]Donahue R N, McLaughlin P J, Zagon I S. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in micel[J].Gynecol Oncol, 2011，122(2):382-388.

[33]Blebea J, Vu J H, Assadnia S, et al. Differential effects of vascular growth factors on arterial and venous angiogenesisl[J].Journal Of Vascular Surgery, 2002，35(3):532-538.

[34]Blebea J, Mazo J E, Kihara T K, et al. Opioid growth factor modulates angiogenesisl[J].Journal Of Vascular Surgery, 2000，32(2):364-373.

[35]McLaughlin P J, Levin R J, Zagon I S. Opioid growth factor (OGF) inhibits the progression of human squamous cell carcinoma of the head and neck transplanted into nude micel[J].Cancer Lett, 2003，199(2):209-217.

[36]Rogosnitzky M, Finegold M J, McLaughlin P J, et al. Opioid growth factor (OGF) for hepatoblastoma: a novel non-toxic treatmentl[J].Invest New Drugs, 2013，31(4):1066-1070.

[37]McLaughlin P J, Zagon I S, Park S S, et al. Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) -opioid growth factor receptor (OGFr) axisl[J].BMC Cancer, 2009，9:369.

[38]Zagon I S, Rahn K A, Bonneau R H, et al. Opioid growth factor suppresses expression of experimental autoimmune encephalomyelitisl[J].Brain Res, 2010，1310:154-161.

[39]Zagon I S, Donahue R N, Bonneau R H, et al. T lymphocyte proliferation is suppressed by the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: implication for the treatment of autoimmune diseasesl[J].Immunobiology, 2011，216(5):579-590.

[40]McLaughlin P J, Jaglowski J R, Verderame M F, et al. Enhanced growth inhibition of squamous cell carcinoma of the head and neck by combination therapy of paclitaxel and opioid growth factorl[J].Int J Oncol, 2005，26(3):809-816.

[41]Sharp B M, McAllen K, Gekker G, et al. Immunofluorescence detection of delta opioid receptors (DOR) on human peripheral blood CD4+T cells and DOR-dependent suppression of HIV-1 expressionl[J].J Immunol, 2001，167(2):1097-1102.

[42]Peterson P K, Gekker G, Lokensgard J R, et al. Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+lymphocytesl[J].Biochem Pharmacol, 2001，61(9):1145-1151.

[43]Li P F, Hao Y S, Zhang F X, et al. Signaling pathway involved in methionine enkephalin-promoted survival of lymphocytes infected by simian immunodeficiency virus in the early stage in vitrol[J].Int Immunopharmacol, 2004，4(1):79-90.

[44]Blalock J E. The immune system as the sixth sensel[J].Journal Of Internal Medicine, 2005，257(2):126-138.

[45]Janson W, Stein C. Peripheral opioid analgesial[J].Curr Pharm Biotechnol, 2003，4(4):270-274.

[46]Owczarek D, Cibor D, Mach T, et al. Met-enkephalins in patients with inflammatory bowel diseasesl[J].Adv Med Sci, 2011，56(2):158-164.

[47]Spetea M, Rydelius G, Nylander I, et al. Alteration in endogenous opioid systems due to chronic inflammatory pain conditionsl[J].Eur J Pharmacol, 2002，435(2-3):245-252.

Advances in the Research of the Immunomodulatory effects of Methionine Enkephalin

FENG Peng-hui, SHAN Feng-ping

(Teach. &Res.Div.ofImmunol.,Coll.ofBasicMed.Sci.,ChinaMed.Uni,Shenyang110122)

Preproenkephalin derived from adrenal gland possessed bioactivity of morphine-like substance of endogenous neuropeptide methionine enkephalin (MENK), is composed of five amino acid residues Tyr-Gly-Gly-Phe-Met. It brought into play of different bio-functions after coupled with seven-transmembrane specific domain G-protein-coupled receptor. At present, much progress has been made in the research of the modulatory effect and mechanism of methionine enkephalin. The regulation on immune system of MENK and the therapy effects of antitumor, autoimmune diseases, AIDS, and other immune-related diseases were summarized in this paper.

methionine enkephalin (MENK); opioid growth factor; opioid peptide; opioid growth factor receptor; immunoregulation

馮鵬輝 男，臨床醫(yī)學(xué)本碩連讀。研究方向抗腫瘤藥物及免疫調(diào)節(jié)。E-mail：438770123@qq.com

* 通訊作者。男，教授，博士生導(dǎo)師。研究方向?yàn)槟[瘤相關(guān)免疫調(diào)節(jié)與治療的研究工作。E-mail：fpshan@mail.cmu.edu.cn

2015-04-27；

2015-05-24

Q939.93;R392.6

A

1005-7021(2015)06-0100-05

10.3969/j.issn.1005-7021.2015.06.020