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IL-6:炎癥級聯(lián)反應重要參與者,功能最多、影響最廣泛的炎癥細胞因子之一!

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IL-6的抗體抑制劑Tocilizumab和Sarilumab,通過(guò)阻斷IL-6信號通路來(lái),治療風(fēng)濕性關(guān)節炎、細胞因子風(fēng)暴和COVID-19肺炎等疾病的臨床應用前景 [1]。IL-6是一種單鏈糖蛋白細胞因子,由多種細胞產(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在調節系統性炎癥反應綜合征、慢性自身免疫性疾病以及腫瘤發(fā)展等方面發(fā)揮著(zhù)關(guān)鍵作用。目前,IL-6作為炎癥級聯(lián)反應重要參與者,是功能最多、影響最廣泛的炎癥細胞因子之一,正成為藥物研發(fā)的重要靶點(diǎn)!


1. 什么是IL-6?

1.1 IL-6的結構

白細胞介素-6(Interleukin-6,IL-6)是最早被發(fā)現的IL-6家族原型成員,其最初被確定為B細胞刺激因子-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)氨基酸組成的信號肽序列,其基因定位于第7號染色體。IL-6的結構包含四個(gè)螺旋束,它們以“上-上-下-下”的拓撲結構排列,并且具有三個(gè)環(huán)狀結構(兩個(gè)較長(cháng)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(guò)與其配體結合,實(shí)現信號傳導 [1-7]。

IL-6的結構

圖1. IL-6的結構 [3]

1.2 IL-6的表達和功能

IL-6是一種由免疫系統中多種細胞分泌的重要細胞因子,包括巨噬細胞和被感染的T細胞等。除了巨噬細胞外,還有許多其他細胞類(lèi)型也能產(chǎn)生IL-6,如腸細胞、肝細胞、肺細胞等。IL-6在維持機體穩態(tài)中起著(zhù)重要作用。當體內因感染或組織損傷而打破穩態(tài)時(shí),IL-6會(huì )立即產(chǎn)生并通過(guò)對急性期反應和免疫應答的激活來(lái)對抗這些緊急壓力,從而有助于宿主防御。然而,IL-6過(guò)度合成及持續表達失調會(huì )導致病理性影響,包括急性期蛋白的產(chǎn)生、炎癥反應、免疫反應、宿主防御和造血等等。自從IL-6被發(fā)現以來(lái),研究人員發(fā)現,IL-6可以與多種疾病密切關(guān)聯(lián)的現象,比如應激、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結合沒(méi)有信號傳導能力的IL-6受體(IL-6R/IL-6Rα,也稱(chēng)為CD126),進(jìn)而結合第二個(gè)受體亞基130(GP130),形成了一個(gè)六聚體復合物,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(lèi)型(IL-6R和sIL-6R),它們分別啟動(dòng)不同的信號轉導通路:膜受體啟動(dòng)經(jīng)典信號途徑;可溶性受體則啟動(dòng)反式信號。兩種類(lèi)型都需要GP130的參與。盡管GP130在細胞中廣泛表達,但IL-6受體/IL-6R僅存在于特定的細胞上,例如肝細胞、中性粒細胞、單核細胞、巨噬細胞以及T和B淋巴細胞等??扇苄訧L-6R通過(guò)與IL-6形成復合物,這一過(guò)程介導了IL-6在表面僅含有GP130的多種細胞(如神經(jīng)細胞、平滑肌細胞和內皮細胞)中的信號傳導 [8-10]。


3. IL-6相關(guān)的信號機制

IL-6通過(guò)其獨特的受體系統傳遞信號。它與IL-6R/IL-6Ra結合蛋白和信號轉導組分糖蛋白130(CD130)組成的細胞表面I型受體復合物相互作用。該復合物IL-6/IL-6R/GP130激活JAK/STAT3、PI3K/AKT/mTOR、RAS/RAF/MEK/ERK、YAP、SHP2/RAS/MAPK等信號通路的激活,也被稱(chēng)為IL-6的經(jīng)典信號轉導 [11]。

3.1 IL-6的經(jīng)典信號轉導

在IL-6經(jīng)典信號轉導中,關(guān)鍵蛋白包括Janus激酶(JAK)、STAT3以及Ras蛋白。IL-6激活JAK和STAT3,導致STAT3磷酸化并形成二聚體,隨后進(jìn)入細胞核調節基因表達,促進(jìn)細胞生長(cháng)、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)轉錄因子活性,參與細胞生長(cháng)、免疫球蛋白合成等過(guò)程。另外,IL-6通過(guò)激活PI3K/PKB/Akt途徑調節信號傳導,影響細胞的生理活性 [10-11]。在未經(jīng)刺激的CD4?T細胞中,IL-6能夠激活STAT3,進(jìn)而誘導STAT3及其靶基因的轉錄,其中包括Arid5a,它保護STAT3 mRNA免受Regnase-1介導的降解作用。Arid5a對IL-6和STAT3 mRNA的調控對于IL-6的生成以及由IL-6受體介導的信號強度至關(guān)重要 [12]。

3.2 IL-6的反式信號傳導

IL-6僅與IL-6R結合,而不與GP130結合,因此IL-6R未表達的細胞對IL-6沒(méi)有反應。然而,膜結合的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ADAM17ADAM10。因為GP130廣泛表達,這種sIL-6R的生成擴展了IL-6的作用范圍。sIL-6R結合GP130而不需要IL-6R的細胞進(jìn)行信號傳導,這稱(chēng)為IL-6的反式信號傳導。因此,IL-6的不同作用途徑調節著(zhù)不同的生物效應,包括控制白細胞招募和腫瘤相關(guān)的炎性反應,在急性期免疫反應、造血功能和中樞平衡過(guò)程中起重要作用 [11]。

3.3 IL-6的其它信號轉導

在正常細胞中,IL-6的產(chǎn)生受到不同信號的調節,如IL-1、TNF、IFNs、DNA病毒、RNA病毒和細菌內毒素等 [13]。在急性炎癥中,單核細胞和巨噬細胞通過(guò)TLR激活I(lǐng)L-6的產(chǎn)生,而在慢性炎癥中,T細胞是IL-6主要來(lái)源之一。研究表明,多聚核苷酸Poly I:C能激活TLR3,從而誘導IL-6自我釋放,并通過(guò)STAT3磷酸化調節TLR2表達量 [14]??傊?,IL-6在生理和病理過(guò)程中扮演復雜角色,針對性地阻斷IL-6及其信號通路已成為治療多種疾病研究的有效策略。

IL-6相關(guān)的信號機制

圖2. IL-6相關(guān)的信號機制 [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的合成和釋放是機體應對損傷或感染的重要反應之一。IL-6可以迅速被激活并釋放到局部組織,隨后通過(guò)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,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)生是機體對抗感染和修復組織損傷的關(guān)鍵步驟,它們不僅參與了免疫反應的調節,還有助于抵御病原體的入侵。通過(guò)調節炎癥反應的程度和持續時(shí)間,有助于維持組織內穩定的環(huán)境。因此,IL-6的早期釋放以及對急性期蛋白的合成對于抵御感染、修復組織損傷以及調節免疫反應至關(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(zhù)一個(gè)多面手的角色。IL-6參與調節骨骼系統的穩態(tài),對破骨細胞的分化與活化發(fā)揮著(zhù)重要作用,進(jìn)而影響骨質(zhì)密度和結構,最終導致骨質(zhì)疏松癥的發(fā)生 [19-20]。IL-6還能夠誘導血管內皮生長(cháng)因子(VEGF)的過(guò)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(lèi)風(fēng)濕性關(guān)節炎的病理過(guò)程中,滑膜組織的血管通透性增加與IL-6誘導的VEGF過(guò)度表達密切相關(guān),加劇了關(guān)節炎的病情 [21-22]。此外,IL-6的產(chǎn)生降低了白蛋白、纖連蛋白和轉鐵蛋白的生成。在慢性炎癥性疾病中,該過(guò)程可能導致嚴重的并發(fā)癥,如罕見(jiàn)病淀粉樣變性 [23]。因此,IL-6的多效性表現不僅僅局限于特定細胞類(lèi)型,而是在整個(gè)炎癥性疾病過(guò)程中發(fā)揮著(zhù)重要作用,其調節作用影響著(zhù)骨骼健康和血管通透性等多個(gè)生理過(guò)程。

4.2 IL-6和神經(jīng)系統研究

IL-6不僅在炎癥性疾病中發(fā)揮作用,近年來(lái)發(fā)現也在神經(jīng)系統中發(fā)揮著(zhù)重要作用。適量的IL-6在神經(jīng)系統內調控神經(jīng)元的發(fā)育、分化和存活過(guò)程,維持神經(jīng)系統的生長(cháng)和正常功能。然而,在遭受炎癥刺激或損傷時(shí),機體會(huì )產(chǎn)生大量的IL-6。過(guò)剩的IL-6通過(guò)致炎作用進(jìn)一步影響神經(jīng)細胞,導致?lián)p傷。新生兒化膿性腦膜炎(NPM)是新生兒期常見(jiàn)的中樞神經(jīng)系統感染性疾病之一。研究提示,在NPM患兒腦脊液中,細胞因子IL-6、IL-10濃度升高,提示其在NPM的發(fā)病機制中發(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(wú)一致結論 [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家族細胞因子一樣,其在癌癥中的表達異常、受體信號失調,與不良臨床結果相關(guān)。IL-6直接影響癌細胞活動(dòng),間接調節基質(zhì)細胞,影響腫瘤微環(huán)境。IL-6通過(guò)激活STAT3等信號通路參與多種致癌機制,包括增強癌細胞生長(cháng)、血管生成、促進(jìn)轉移和侵襲。在晚期,IL-6促進(jìn)癌細胞的轉移和擴散,促進(jìn)癌癥干細胞的增殖和種群擴張。其他IL-6家族成員如IL-11、LIF和OSM也與腫瘤生長(cháng)相關(guān)。IL-6濃度與多種腫瘤的患病率、預后密切相關(guān),可能成為腫瘤預后的獨立指標 [29-30]。

舉例來(lái)說(shuō),研究發(fā)現,結直腸腺瘤與血清IL-6濃度升高相關(guān),晚期直腸癌患者的IL-6水平顯著(zhù)高于早期患者,并且與患者的預后密切相關(guān)。然而,IL-6濃度不能單獨預測結直腸癌的狀態(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志,具有預后價(jià)值 [32];肝癌組織中IL-6水平升高與不良預后相關(guān),可能成為肝癌病人預后的獨立指標 [33];IL-6的分泌促使STAT3磷酸化,增強前列腺癌細胞的增殖和遷移能力,并同時(shí)抑制細胞的凋亡和上皮間質(zhì)轉化(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)險增加相關(guān),其作用可導致血管平滑肌細胞轉化為成骨樣細胞,促進(jìn)血管內鈣鹽沉積 [35-36]。另一方面,IL-6具有極強的致炎敏感性和特異性,它可以促使滑膜和軟骨細胞釋放炎性遞質(zhì),從而減少滑膜炎癥反應,降低骨關(guān)節炎軟骨的損傷 [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(guò)程中的具體作用機制,如參與內皮屏障功能障礙、心肌負性肌力效應、血管內皮生長(cháng)因子誘導VE-cadherin磷酸化、以及在急性淋巴細胞白血病等惡性腫瘤治療中使用CAR-T細胞療法時(shí)所伴隨的細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信號在巨噬細胞替代激活途徑中限制內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)生鐵調節激素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出相當活躍和潛力。靶向IL-6的主要方法是使用IL-6受體(IL-6R)的單克隆抗體,目前已批準上市的藥物有3種,如托珠單抗(Tocilizumab)。Tocilizumab通過(guò)結合IL-6結合位點(diǎn)上的IL-6R來(lái)中和IL-6的活性,從而阻斷信號傳導。自托珠單抗應用于臨床治療以來(lái),已成功治療多種疾病,如類(lèi)風(fēng)濕關(guān)節炎、系統性關(guān)節炎等,并表現出顯著(zhù)的療效。當前,針對IL-6的治療策略已成功應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用。在藥物研發(fā)國家中,美國和中國占據了領(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。預計在未來(lái)十年內,IL-6抑制劑將廣泛應用于目前難以治療的各種疾病,包括細胞因子風(fēng)暴,并有望克服這類(lèi)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。

產(chǎn)品力薦

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Recombinant Human Interleukin-6(IL6) (Active) Code: CSB-YP011664HU

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Immobilized Human IL6 at 2μg/mL can bind Anti-IL6 recombinant antibody (CSB-RA011664MA1HU). The EC50 is 35.80-41.82 ng/mL.


參考文獻:

[1] Wang, Mingxing, et al. "Structural insights into IL-6 signaling inhibition by therapeutic antibodies." Cell Reports 43.3 (2024).

[2] Tanaka, Toshio, Atsushi Ogata, and Masashi Narazaki. "Tocilizumab: an updated review of its use in the treatment of rheumatoid arthritis and its application for other immune-mediated diseases." Clinical Medicine Insights: Therapeutics 5 (2013): CMT-S9282.

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