IL-6：炎癥級(jí)聯(lián)反應(yīng)重要參與者，功能最多、影響最廣泛的炎癥細(xì)胞因子之一！
日期：2024-04-11 09:59:36
2024年2月22日，Cell Reports雜志刊登了題為“Structural insights into IL-6 signaling inhibition by therapeutic antibodies”的文章，揭示了針對(duì)IL-6的抗體抑制劑Tocilizumab和Sarilumab，通過阻斷IL-6信號(hào)通路來，治療風(fēng)濕性關(guān)節(jié)炎、細(xì)胞因子風(fēng)暴和COVID-19肺炎等疾病的臨床應(yīng)用前景 [1]。IL-6是一種單鏈糖蛋白細(xì)胞因子，由多種細(xì)胞產(chǎn)生，具有廣泛的生物學(xué)活性功能。大量的研究證實(shí)，IL-6在調(diào)節(jié)系統(tǒng)性炎癥反應(yīng)綜合征、慢性自身免疫性疾病以及腫瘤發(fā)展等方面發(fā)揮著關(guān)鍵作用。目前，IL-6作為炎癥級(jí)聯(lián)反應(yīng)重要參與者，是功能最多、影響最廣泛的炎癥細(xì)胞因子之一，正成為藥物研發(fā)的重要靶點(diǎn)！
1. 什么是IL-6？
1.1 IL-6的結(jié)構(gòu)
白細(xì)胞介素-6（Interleukin-6，IL-6）是最早被發(fā)現(xiàn)的IL-6家族原型成員，其最初被確定為B細(xì)胞刺激因子-2（BSF-2）。IL-6分子量約為26 kDa，屬于磷酸化糖蛋白。人IL-6由212個(gè)氨基酸組成，其中包括28個(gè)氨基酸組成的信號(hào)肽序列，其基因定位于第7號(hào)染色體。IL-6的結(jié)構(gòu)包含四個(gè)螺旋束，它們以“上-上-下-下”的拓?fù)浣Y(jié)構(gòu)排列，并且具有三個(gè)環(huán)狀結(jié)構(gòu)（兩個(gè)較長的環(huán)，分別為A-B環(huán)和C-D環(huán)，以及一個(gè)較短的B-C環(huán)）。IL-6家族細(xì)胞因子包括IL-6、IL-11、IL-27、OSM、LIF、CNTF、CT1、CLCF1、IL-35、IL-39等10個(gè)成員。這些成員雖然在序列上并不相同，但它們都基于了共同的受體亞單位，即受體膜糖蛋白130（GP130），再通過與其配體結(jié)合，實(shí)現(xiàn)信號(hào)傳導(dǎo) [1-7]。
圖1. IL-6的結(jié)構(gòu) [3]
1.2 IL-6的表達(dá)和功能
IL-6是一種由免疫系統(tǒng)中多種細(xì)胞分泌的重要細(xì)胞因子，包括巨噬細(xì)胞和被感染的T細(xì)胞等。除了巨噬細(xì)胞外，還有許多其他細(xì)胞類型也能產(chǎn)生IL-6，如腸細(xì)胞、肝細(xì)胞、肺細(xì)胞等。IL-6在維持機(jī)體穩(wěn)態(tài)中起著重要作用。當(dāng)體內(nèi)因感染或組織損傷而打破穩(wěn)態(tài)時(shí)，IL-6會(huì)立即產(chǎn)生并通過對(duì)急性期反應(yīng)和免疫應(yīng)答的激活來對(duì)抗這些緊急壓力，從而有助于宿主防御。然而，IL-6過度合成及持續(xù)表達(dá)失調(diào)會(huì)導(dǎo)致病理性影響，包括急性期蛋白的產(chǎn)生、炎癥反應(yīng)、免疫反應(yīng)、宿主防御和造血等等。自從IL-6被發(fā)現(xiàn)以來，研究人員發(fā)現(xiàn)，IL-6可以與多種疾病密切關(guān)聯(lián)的現(xiàn)象，比如應(yīng)激、肺炎、免疫、心血管以及腫瘤等 [1-7]。
2. IL-6的受體是什么？
IL-6結(jié)合沒有信號(hào)傳導(dǎo)能力的IL-6受體（IL-6R/IL-6Rα，也稱為CD126），進(jìn)而結(jié)合第二個(gè)受體亞基130（GP130），形成了一個(gè)六聚體復(fù)合物，由2個(gè)配體分子、2個(gè)α亞基分子和2個(gè)β130分子組成。IL-6的受體有兩種類型（IL-6R和sIL-6R），它們分別啟動(dòng)不同的信號(hào)轉(zhuǎn)導(dǎo)通路：膜受體啟動(dòng)經(jīng)典信號(hào)途徑；可溶性受體則啟動(dòng)反式信號(hào)。兩種類型都需要GP130的參與。盡管GP130在細(xì)胞中廣泛表達(dá)，但I(xiàn)L-6受體/IL-6R僅存在于特定的細(xì)胞上，例如肝細(xì)胞、中性粒細(xì)胞、單核細(xì)胞、巨噬細(xì)胞以及T和B淋巴細(xì)胞等。可溶性IL-6R通過與IL-6形成復(fù)合物，這一過程介導(dǎo)了IL-6在表面僅含有GP130的多種細(xì)胞（如神經(jīng)細(xì)胞、平滑肌細(xì)胞和內(nèi)皮細(xì)胞）中的信號(hào)傳導(dǎo) [8-10]。
3. IL-6相關(guān)的信號(hào)機(jī)制
IL-6通過其獨(dú)特的受體系統(tǒng)傳遞信號(hào)。它與IL-6R/IL-6Ra結(jié)合蛋白和信號(hào)轉(zhuǎn)導(dǎo)組分糖蛋白130（CD130）組成的細(xì)胞表面I型受體復(fù)合物相互作用。該復(fù)合物IL-6/IL-6R/GP130激活JAK/STAT3、PI3K/AKT/mTOR、RAS/RAF/MEK/ERK、YAP、SHP2/RAS/MAPK等信號(hào)通路的激活，也被稱為IL-6的經(jīng)典信號(hào)轉(zhuǎn)導(dǎo) [11]。
3.1 IL-6的經(jīng)典信號(hào)轉(zhuǎn)導(dǎo)
在IL-6經(jīng)典信號(hào)轉(zhuǎn)導(dǎo)中，關(guān)鍵蛋白包括Janus激酶（JAK）、STAT3以及Ras蛋白。IL-6激活JAK和STAT3，導(dǎo)致STAT3磷酸化并形成二聚體，隨后進(jìn)入細(xì)胞核調(diào)節(jié)基因表達(dá)，促進(jìn)細(xì)胞生長、分化和存活。此外，IL-6也激活Ras蛋白，進(jìn)而增加MAPK活性，促進(jìn)轉(zhuǎn)錄因子活性，參與細(xì)胞生長、免疫球蛋白合成等過程。另外，IL-6通過激活PI3K/PKB/Akt途徑調(diào)節(jié)信號(hào)傳導(dǎo)，影響細(xì)胞的生理活性 [10-11]。在未經(jīng)刺激的CD4?T細(xì)胞中，IL-6能夠激活STAT3，進(jìn)而誘導(dǎo)STAT3及其靶基因的轉(zhuǎn)錄，其中包括Arid5a，它保護(hù)STAT3 mRNA免受Regnase-1介導(dǎo)的降解作用。Arid5a對(duì)IL-6和STAT3 mRNA的調(diào)控對(duì)于IL-6的生成以及由IL-6受體介導(dǎo)的信號(hào)強(qiáng)度至關(guān)重要 [12]。
3.2 IL-6的反式信號(hào)傳導(dǎo)
IL-6僅與IL-6R結(jié)合，而不與GP130結(jié)合，因此IL-6R未表達(dá)的細(xì)胞對(duì)IL-6沒有反應(yīng)。然而，膜結(jié)合的IL-6R可以被蛋白水解酶切割，釋放出與IL-6相互作用的可溶性IL-6R（sIL-6R），其主要的酶是ADAM17和ADAM10。因?yàn)镚P130廣泛表達(dá)，這種sIL-6R的生成擴(kuò)展了IL-6的作用范圍。sIL-6R結(jié)合GP130而不需要IL-6R的細(xì)胞進(jìn)行信號(hào)傳導(dǎo)，這稱為IL-6的反式信號(hào)傳導(dǎo)。因此，IL-6的不同作用途徑調(diào)節(jié)著不同的生物效應(yīng)，包括控制白細(xì)胞招募和腫瘤相關(guān)的炎性反應(yīng)，在急性期免疫反應(yīng)、造血功能和中樞平衡過程中起重要作用 [11]。
3.3 IL-6的其它信號(hào)轉(zhuǎn)導(dǎo)
在正常細(xì)胞中，IL-6的產(chǎn)生受到不同信號(hào)的調(diào)節(jié)，如IL-1、TNF、IFNs、DNA病毒、RNA病毒和細(xì)菌內(nèi)毒素等 [13]。在急性炎癥中，單核細(xì)胞和巨噬細(xì)胞通過TLR激活I(lǐng)L-6的產(chǎn)生，而在慢性炎癥中，T細(xì)胞是IL-6主要來源之一。研究表明，多聚核苷酸Poly I:C能激活TLR3，從而誘導(dǎo)IL-6自我釋放，并通過STAT3磷酸化調(diào)節(jié)TLR2表達(dá)量 [14]?？傊琁L-6在生理和病理過程中扮演復(fù)雜角色，針對(duì)性地阻斷IL-6及其信號(hào)通路已成為治療多種疾病研究的有效策略。
圖2. IL-6相關(guān)的信號(hào)機(jī)制 [11]
4. IL-6和疾病相關(guān)的研究
4.1 IL-6和炎癥研究
4.1.1 IL-6在急性炎癥中的研究
在炎癥早期，IL-6的合成和釋放是機(jī)體應(yīng)對(duì)損傷或感染的重要反應(yīng)之一。IL-6可以迅速被激活并釋放到局部組織，隨后通過血液循環(huán)迅速傳播到全身各個(gè)部位。在肝臟中，IL-6的產(chǎn)生可引發(fā)一系列生物學(xué)反應(yīng)，其中包括急性期蛋白的合成，其中包括CRP、SAA和纖維蛋白原等。這些急性期蛋白的產(chǎn)生是機(jī)體對(duì)抗感染和修復(fù)組織損傷的關(guān)鍵步驟，它們不僅參與了免疫反應(yīng)的調(diào)節(jié)，還有助于抵御病原體的入侵。通過調(diào)節(jié)炎癥反應(yīng)的程度和持續(xù)時(shí)間，有助于維持組織內(nèi)穩(wěn)定的環(huán)境。因此，IL-6的早期釋放以及對(duì)急性期蛋白的合成對(duì)于抵御感染、修復(fù)組織損傷以及調(diào)節(jié)免疫反應(yīng)至關(guān)重要 [15-18]。
4.1.2 IL-6在慢性炎癥中的研究
IL-6在慢性炎癥中扮演著一個(gè)多面手的角色。IL-6參與調(diào)節(jié)骨骼系統(tǒng)的穩(wěn)態(tài)，對(duì)破骨細(xì)胞的分化與活化發(fā)揮著重要作用，進(jìn)而影響骨質(zhì)密度和結(jié)構(gòu)，最終導(dǎo)致骨質(zhì)疏松癥的發(fā)生 [19-20]。IL-6還能夠誘導(dǎo)血管內(nèi)皮生長因子（VEGF）的過度產(chǎn)生，這會(huì)增加血管通透性，成為炎癥性疾病的典型特征之一。例如，在類風(fēng)濕性關(guān)節(jié)炎的病理過程中，滑膜組織的血管通透性增加與IL-6誘導(dǎo)的VEGF過度表達(dá)密切相關(guān)，加劇了關(guān)節(jié)炎的病情 [21-22]。此外，IL-6的產(chǎn)生降低了白蛋白、纖連蛋白和轉(zhuǎn)鐵蛋白的生成。在慢性炎癥性疾病中，該過程可能導(dǎo)致嚴(yán)重的并發(fā)癥，如罕見病淀粉樣變性 [23]。因此，IL-6的多效性表現(xiàn)不僅僅局限于特定細(xì)胞類型，而是在整個(gè)炎癥性疾病過程中發(fā)揮著重要作用，其調(diào)節(jié)作用影響著骨骼健康和血管通透性等多個(gè)生理過程。
4.2 IL-6和神經(jīng)系統(tǒng)研究
IL-6不僅在炎癥性疾病中發(fā)揮作用，近年來發(fā)現(xiàn)也在神經(jīng)系統(tǒng)中發(fā)揮著重要作用。適量的IL-6在神經(jīng)系統(tǒng)內(nèi)調(diào)控神經(jīng)元的發(fā)育、分化和存活過程，維持神經(jīng)系統(tǒng)的生長和正常功能。然而，在遭受炎癥刺激或損傷時(shí)，機(jī)體會(huì)產(chǎn)生大量的IL-6。過剩的IL-6通過致炎作用進(jìn)一步影響神經(jīng)細(xì)胞，導(dǎo)致?lián)p傷。新生兒化膿性腦膜炎（NPM）是新生兒期常見的中樞神經(jīng)系統(tǒng)感染性疾病之一。研究提示，在NPM患兒腦脊液中，細(xì)胞因子IL-6、IL-10濃度升高，提示其在NPM的發(fā)病機(jī)制中發(fā)揮一定作用 [24-25]。此外，IL-6水平在熱性驚厥患兒中明顯升高，尤其是復(fù)雜性熱性驚厥患兒。雖然IL-6基因存在多種位點(diǎn)，但其與熱性驚厥易感性之間的關(guān)系尚無一致結(jié)論 [26-28]。
4.3 IL-6在腫瘤晚期中的研究
IL-6在腫瘤晚期扮演重要角色，與其他IL-6家族細(xì)胞因子一樣，其在癌癥中的表達(dá)異常、受體信號(hào)失調(diào)，與不良臨床結(jié)果相關(guān)。IL-6直接影響癌細(xì)胞活動(dòng)，間接調(diào)節(jié)基質(zhì)細(xì)胞，影響腫瘤微環(huán)境。IL-6通過激活STAT3等信號(hào)通路參與多種致癌機(jī)制，包括增強(qiáng)癌細(xì)胞生長、血管生成、促進(jìn)轉(zhuǎn)移和侵襲。在晚期，IL-6促進(jìn)癌細(xì)胞的轉(zhuǎn)移和擴(kuò)散，促進(jìn)癌癥干細(xì)胞的增殖和種群擴(kuò)張。其他IL-6家族成員如IL-11、LIF和OSM也與腫瘤生長相關(guān)。IL-6濃度與多種腫瘤的患病率、預(yù)后密切相關(guān)，可能成為腫瘤預(yù)后的獨(dú)立指標(biāo) [29-30]。
舉例來說，研究發(fā)現(xiàn)，結(jié)直腸腺瘤與血清IL-6濃度升高相關(guān)，晚期直腸癌患者的IL-6水平顯著高于早期患者，并且與患者的預(yù)后密切相關(guān)。然而，IL-6濃度不能單獨(dú)預(yù)測結(jié)直腸癌的狀態(tài) [31]；胃癌患者研究表明，胃黏膜中的IL-6水平與存活時(shí)間密切相關(guān)，提示IL-6可能是腫瘤侵襲的標(biāo)志，具有預(yù)后價(jià)值 [32]；肝癌組織中IL-6水平升高與不良預(yù)后相關(guān)，可能成為肝癌病人預(yù)后的獨(dú)立指標(biāo) [33]；IL-6的分泌促使STAT3磷酸化，增強(qiáng)前列腺癌細(xì)胞的增殖和遷移能力，并同時(shí)抑制細(xì)胞的凋亡和上皮間質(zhì)轉(zhuǎn)化（EMT） [34]。
4.4 IL-6和其它相關(guān)疾病研究
高水平的IL-6與冠心病風(fēng)險(xiǎn)增加相關(guān)，其作用可導(dǎo)致血管平滑肌細(xì)胞轉(zhuǎn)化為成骨樣細(xì)胞，促進(jìn)血管內(nèi)鈣鹽沉積 [35-36]。另一方面，IL-6具有極強(qiáng)的致炎敏感性和特異性，它可以促使滑膜和軟骨細(xì)胞釋放炎性遞質(zhì)，從而減少滑膜炎癥反應(yīng)，降低骨關(guān)節(jié)炎軟骨的損傷 [37]。同時(shí)，IL-6還能阻止蛋白聚糖和軟骨膠原的合成，有效抑制骨細(xì)胞的活性 [38-39]。IL-6還與胎糞吸入綜合征、睡眠呼吸暫停相關(guān)的肺動(dòng)脈高壓等疾病密切相關(guān)，其相關(guān)作用機(jī)制需進(jìn)一步研究 [40-42]。
一些研究也在探索靶向IL-6在其它病理過程中的具體作用機(jī)制，如參與內(nèi)皮屏障功能障礙、心肌負(fù)性肌力效應(yīng)、血管內(nèi)皮生長因子誘導(dǎo)VE-cadherin磷酸化、以及在急性淋巴細(xì)胞白血病等惡性腫瘤治療中使用CAR-T細(xì)胞療法時(shí)所伴隨的細(xì)胞因子釋放綜合癥管理等方面的研究 [43-46]。同時(shí)指出IL-6信號(hào)在巨噬細(xì)胞替代激活途徑中限制內(nèi)毒素血癥和肥胖相關(guān)胰島素抵抗方面的作用 [47-48]。此外，IL-6可促使產(chǎn)生鐵調(diào)節(jié)激素hepcidin，影響血液中的鐵和鋅水平，引發(fā)貧血和低鋅血癥 [49-50]。
5. IL-6的臨床研究前景
IL-6的臨床研究前景呈現(xiàn)出相當(dāng)活躍和潛力。靶向IL-6的主要方法是使用IL-6受體（IL-6R）的單克隆抗體，目前已批準(zhǔn)上市的藥物有3種，如托珠單抗（Tocilizumab）。Tocilizumab通過結(jié)合IL-6結(jié)合位點(diǎn)上的IL-6R來中和IL-6的活性，從而阻斷信號(hào)傳導(dǎo)。自托珠單抗應(yīng)用于臨床治療以來，已成功治療多種疾病，如類風(fēng)濕關(guān)節(jié)炎、系統(tǒng)性關(guān)節(jié)炎等，并表現(xiàn)出顯著的療效。當(dāng)前，針對(duì)IL-6的治療策略已成功應(yīng)用于若干慢性自身免疫性疾病，并有望在更多疾病的治療中得到廣泛應(yīng)用。在藥物研發(fā)國家中，美國和中國占據(jù)了領(lǐng)先地位，在該賽道上是最具競爭力的國家，值得關(guān)注和重視。預(yù)計(jì)在未來十年內(nèi)，IL-6抑制劑將廣泛應(yīng)用于目前難以治療的各種疾病，包括細(xì)胞因子風(fēng)暴，并有望克服這類疾病的難治性。綜上所述，該賽道的藥物研發(fā)進(jìn)展較好，具有較高的可行性。
為鼎力協(xié)助各藥企針對(duì)IL6在系統(tǒng)性炎癥反應(yīng)綜合征、慢性自身免疫性疾病以及腫瘤等在臨床中的研究，華美CUSABIO推出IL6（CSB-YP011664HU）活性蛋白產(chǎn)品，助力您在對(duì)IL6機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
華美CUSABIO蛋白IL6
Recombinant Human Interleukin-6(IL6) (Active) Code: CSB-YP011664HU
Purity was greater than 90% as determined by SDS-PAGE.
Immobilized Human IL6 at 2μg/mL can bind Anti-IL6 recombinant antibody (CSB-RA011664MA1HU). The EC50 is 35.80-41.82 ng/mL.
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