肝纤维化与TNF-α,IL-6及IL-10
福建医科大学附属协和医院消化内科 福建省福州市 350001
项目负责人 李丹 Tel. 0086-591-3357896 Ext.8482
Email. fzsmile@hotmail.com
收稿日期 2001-03-28 接受日期 2001-04-18
主题词 肝硬化/病理生理学；肿瘤坏死因子；白细胞介素6；白细胞介素10
李丹, 王小众. 肝纤维化与TNF-α, IL-6及IL-10. 世界华人消化杂志，2001；9(7)：808-810
肝纤维化(LF)是各种原因引起的慢性肝损伤所共有的细胞病理过程，其特征为大量细胞外 基质(ECM)在Disse间隙沉积[1-5]. 近来，由于细胞生物学及细胞因子信号传导研 究领域中取得的重大进展，越来越多的证据表明，肝纤维化是可以逆转的[6-10]. 各种细胞因子通过复杂的调节机制在肝纤维化的进展中起重要作用[11-15]，从而使对细胞因子和肝纤维化的研究成为热点之一.
1 肿瘤坏死因子α(TNF-α)1975年Garswell et al给实验性诱生肿瘤的动物注射卡介苗后又注射内毒素，在血清中发现一种可引起肿瘤坏死出血的活性因子，命名为肿瘤坏死因子(TNF). TNF具有复杂的生物学活性，包括抗肿瘤、抗病毒、免疫调节和诱发炎症反应等[16,17]. TNF尤其是TNF-α在肝纤维化的发生发展中占重要地位[18,19]. 各种原因引起肝 脏疾病时，肝实质细胞和库普弗细胞在内毒素的介导下产生多种细胞因子，包括TNF-α[20,21]. 病毒性肝炎后肝硬变患者[22-24]及实验性肝纤维化动物模型 中[25]血清TNF-α均升高，Kimura et al[26]报道对因每 周注射刀豆蛋白A而致肝纤维化的BALB/C小鼠予以抗TNF-α抗体干预后，能阻止肝纤维化的发展. 实验证明小鼠单独腹腔注射TNF-α不能引起明显的肝损害，但予GalN或AtD协同刺激后，TNF-α就表现出明显的细胞毒作用，这表明TNF-α虽参与对肝细胞的损害，但需要其他因素如内毒素，D-氨基半乳糖或病毒等的协同作用[27]，而这种作用 是在转录水平上进行调控的，也称为转录捕获[28]. TNF-α通过多种机制参于肝 纤维化的调控，其中心环节是激活肝星形细胞(HSC)，而星形细胞的激活在肝纤维化中的主导地位已是不争的事实[29-34]. TNF-α能激活转录因子AP-1和c-jun激酶，导致基质金属蛋白酶(MMPs)表达增加[35]胶原基因表达下降[36] ；介导脂类递质或其他肽类递质产生，诱导自由基的产生和脂质过氧化[37]； 刺激产生单核细胞趋化因子[38]及中性粒细胞趋化因子[39]，趋化因子 能引起白细胞在损伤部位聚集，加速肝纤维化的进展；促使活化的肝星形细胞自分泌多种细 胞因子如IL-6, IL-10, EGF, ET-1, TGF等，发挥各种生物学活性[40]. 近年来，TNF-α对细胞凋亡的介导作用受到关注[41-43]. 最近动物实验[28] 及体外细胞培养[44]表明TNF-α在转录抑制剂的协同作用下可直接引起小鼠肝细 胞的凋亡. Takei et al[45]证明抗TNF-α抗体可阻止GalN引起的肝细胞凋亡 ，防止暴发性肝衰竭发生. Lang et al[46]研究了TNF-α与肝星形细胞凋亡 的关系，结果表明，TNF-α对已激活的肝星形细胞可产生凋亡诱导，此作用能被TNF-α的主要下游效应物NF-kB所阻断. NF-kB对肝脏再生及炎症反应均有调节作用[47]，它能通过其产生的一组基因产物的协同作用抑制TNF-α诱发的Caspase-8激活来阻止凋 亡[48]，这是一种负反馈机制. 由于在肝纤维化恢复期，激活状态的肝星形细胞减少主要通过凋亡机制而非表型逆转[49]，加强对TNF-α介导的星形细胞凋亡机 制研究将有助于指导未来抗纤维化的治疗策略.
2 白介素
2.1 白介素6 (IL-6) 白介素6(IL-6) 作为一种具有多种生物学功能的细胞因子[50]，在肝脏的生理和病理过程中的作用已引起广大学者的关注[51-53]. 活化的肝星形细胞和肝成纤维细胞是肝脏IL-6的主要来源，LPS, IL-1β, TNF-α均是上述二类细胞合成分泌IL-6的有效刺激物，这已在体外培养人肝脏贮脂细胞和成纤维细胞的实验中得到证实[54]. NF-kB也可通过促进IL-6基因转录进一步扩大炎症反应[55]. 对急、慢性肝病患者的肝脏病理标本以IL-6单克隆抗体行免疫荧光检测发现肝脏病理状态下局部分泌IL-6增多，促进炎症发展和免疫反应[56]. 国内外报道肝炎病毒感染后肝硬变及酒精性肝硬变患者血清 中IL-6含量均高于正常对照组[57,58]，且丙型肝炎病毒感染后肝硬变>酒精性硬变. 国内甄真et al[59]报道同正常对照组相比，病毒性肝炎患者IL-6活性和可溶性白介素6受体(sIL-6R)水平均明显升高，依次为慢性重型肝炎>肝炎后肝硬 变(活动性)>慢性肝炎(重度)>慢性肝炎(中度)>急性黄疸型肝炎>慢性肝炎(轻度)，其中慢性重型肝炎又明显高于其他各组，提示血清IL-6和sIL-6R的升高与肝细胞坏死密切相关. IL-6和IL-1β, TNF-α均为肝实质细胞合成急性相反应蛋白的强力诱导剂[ 60-62]，急性相反应蛋白通过抑制蛋白酶、加强α1(Ⅰ)型前胶原及组 织金属蛋白酶抑制物(TIMP)的转录表达及增强损伤因子的作用维持或加速肝纤维化的进 展[63,64]；IL-6也能直接刺激肝细胞上调TIMP-1的表达[65]. Cressman et al[66]发现IL-6基因敲除小鼠行部分肝切除后，由于肝细胞增殖能力缺陷，导致小鼠肝坏死和肝衰竭，而在手术前单次予定量IL-6注射后，术后小鼠 肝组织能恢复到接近正常水平，提示IL-6是损 伤后促进细胞增殖的重要物质. Natsume et al[67]报道CCl4诱导的IL-6基 因敲除小鼠较正常对照组肝纤维化损害轻，且伴有肝细胞生长因子(HGF)和生长转化因子β1(TGF-β1)的表达下降，故认为肝纤维化早期，IL-6基因表达增强，并通过调节肝内其他细胞因子的表达来参与纤维化进程，其同TNF-α, IL-3, IL-4, IL-5, IL-8等细胞因子均存在协同作用[68,69]. 此外，近来有资料表明IL-6还可能通 过Fas途径调节肝星形细胞的凋亡[70].
2.2 白介素10(IL-10) 引发和促进炎症和纤维化反 应的细胞因子在目前的研究中倍受瞩目，事实上，同其相拮抗的细胞因子也同等重要. IL-10在起抗炎、抗纤维化作用的免疫调节因子中占突出地位[71-73]，主要由TH2细胞，巨噬细胞，肥大细胞[74]，肝细胞[75]及肝星形细胞[76]等产生. 动物模型[25]和细胞培养[77]均证实在肝纤维化时IL-10的表达增高，TNF-α, TGF-β, LPS在体外均能促进活化的星形细胞合成并分泌IL-10，且分泌量随活化的细胞数增多而升高，但当肝纤维化进展到肝硬变时，IL-10的合成量渐下降. IL-10具有复杂而广泛的生物学功能：抑制TH1细胞产生IL-2和INF-γ,发挥抗炎作用[78]； 刺激肥大细胞的增殖和蛋白酶的表达[79]；下调巨 噬细胞的功能表达，包括Π形组织相容性抗原的提呈[80,81]、NO的分泌[82 ]及类花生酸物质的合成[83,84]；抑制单核细胞表达ICAM-1, BT等粘附分子[85]，阻止T细胞、中性粒细胞和肌成纤维细胞合成趋化因子[86,87]； 对许多细胞特别是单核细胞和巨噬细胞，具广泛抑制其合成化学致炎因子的作用[88]；刺激胶原酶，主要是金属蛋白酶Ⅰ(MMP-Ⅰ)的合成并抑制α1(Ⅰ)型胶原的转录合 成[77]，缓解胶原的大量沉积. Thompson et al[89]报道IL-10基因敲除小鼠予CCl4诱导后，血清检测及病理均证实其纤维化病损较正常对照组明显加重，且近来已有IL-10试用于临床治疗肝纤维化的报道[90]. 可见，IL-10通过多种调节机制参与肝纤维化进程，其在炎症因子所致肝纤维化中的抗纤维化作用已较为肯定[91,92].
3 TNF-α, IL-6及IL-10的相互关系各类细胞因子形成一个复杂的网络来调节肝纤维化的发生发展，每个细胞因子不是孤立的发 挥作用，而同其他细胞因子之间存在千丝万缕的联系. 肝纤维化发病中，TNF-α,IL-6及IL-10之间的联系值得关注. 肝病初期，TNF-α通过其主要下游效应物NF-kB活化星形细 胞，自分泌IL-6及IL-10等细胞因子[93-95]，NF-kB还可作用于IL-6基因启动子上的顺式调控序列，从而实现转录和转录后水平的调控[96,97]. IL -6对TNF-α存在微妙的双向调节作用，Mizuhara[98]通过注射刀豆蛋白A建立小 鼠肝细胞损害模型，证明TNF-α是诱导肝损害的主要细胞因子，但在注射刀豆蛋白A前注射一次IL-6可部分抑制TNF-α作用. 这可能是因为IL-6诱导合成急性相反应蛋白中包括 蛋白酶抑制剂，而TNF-α的细胞毒作用部分依赖蛋白酶. IL-6对TNF-α的作用具有时相 性，若在注射刀豆蛋白A后应用IL-6反而加重肝损，这可能同其增加肝TNF-α受体表达有 关. 由于TNF-α在注射刀豆蛋白A早期产生，稍后再予以IL-6不能抑制TNF-α的活性反而通过上调其受体加强TNF-α的细胞毒性作用. Louis et al[99]发现CCl4诱导肝纤维化的C57Bl/6IL-10基因敲除小鼠血清TNF-α和TGF-β1较正常对照组明显升高，病理提示进展性中央小叶炎性浸润及增生反应增强，纤维化病损明显加重；且Wang et al[100]报道IL-10能下调TNF-α下游效应物NF- kB的表达，因此，内源性IL-10可能部分通过调控TNF信号通路来局限细胞增殖和纤维化的进展. 肝纤维化进程中，IL-10通过抑制巨噬细胞释放TNF-α或下调NF-kB减轻炎症反应 ，而IL-6通过上调TNF-α受体等机制加强TNF-α的生物活性，在这个TNF信号环路中，NF-kB是中心环节，抑制NF-kB代表了阻断肝纤维化的重要靶向. 由此可见，深入阐明细胞因子及其网络的相互作用必将为治疗肝纤维化提供更为广阔的前景.
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项目负责人 李丹 Tel. 0086-591-3357896 Ext.8482
Email. fzsmile@hotmail.com
收稿日期 2001-03-28 接受日期 2001-04-18
主题词 肝硬化/病理生理学；肿瘤坏死因子；白细胞介素6；白细胞介素10
李丹, 王小众. 肝纤维化与TNF-α, IL-6及IL-10. 世界华人消化杂志，2001；9(7)：808-810
肝纤维化(LF)是各种原因引起的慢性肝损伤所共有的细胞病理过程，其特征为大量细胞外 基质(ECM)在Disse间隙沉积[1-5]. 近来，由于细胞生物学及细胞因子信号传导研 究领域中取得的重大进展，越来越多的证据表明，肝纤维化是可以逆转的[6-10]. 各种细胞因子通过复杂的调节机制在肝纤维化的进展中起重要作用[11-15]，从而使对细胞因子和肝纤维化的研究成为热点之一.
1 肿瘤坏死因子α(TNF-α)1975年Garswell et al给实验性诱生肿瘤的动物注射卡介苗后又注射内毒素，在血清中发现一种可引起肿瘤坏死出血的活性因子，命名为肿瘤坏死因子(TNF). TNF具有复杂的生物学活性，包括抗肿瘤、抗病毒、免疫调节和诱发炎症反应等[16,17]. TNF尤其是TNF-α在肝纤维化的发生发展中占重要地位[18,19]. 各种原因引起肝 脏疾病时，肝实质细胞和库普弗细胞在内毒素的介导下产生多种细胞因子，包括TNF-α[20,21]. 病毒性肝炎后肝硬变患者[22-24]及实验性肝纤维化动物模型 中[25]血清TNF-α均升高，Kimura et al[26]报道对因每 周注射刀豆蛋白A而致肝纤维化的BALB/C小鼠予以抗TNF-α抗体干预后，能阻止肝纤维化的发展. 实验证明小鼠单独腹腔注射TNF-α不能引起明显的肝损害，但予GalN或AtD协同刺激后，TNF-α就表现出明显的细胞毒作用，这表明TNF-α虽参与对肝细胞的损害，但需要其他因素如内毒素，D-氨基半乳糖或病毒等的协同作用[27]，而这种作用 是在转录水平上进行调控的，也称为转录捕获[28]. TNF-α通过多种机制参于肝 纤维化的调控，其中心环节是激活肝星形细胞(HSC)，而星形细胞的激活在肝纤维化中的主导地位已是不争的事实[29-34]. TNF-α能激活转录因子AP-1和c-jun激酶，导致基质金属蛋白酶(MMPs)表达增加[35]胶原基因表达下降[36] ；介导脂类递质或其他肽类递质产生，诱导自由基的产生和脂质过氧化[37]； 刺激产生单核细胞趋化因子[38]及中性粒细胞趋化因子[39]，趋化因子 能引起白细胞在损伤部位聚集，加速肝纤维化的进展；促使活化的肝星形细胞自分泌多种细 胞因子如IL-6, IL-10, EGF, ET-1, TGF等，发挥各种生物学活性[40]. 近年来，TNF-α对细胞凋亡的介导作用受到关注[41-43]. 最近动物实验[28] 及体外细胞培养[44]表明TNF-α在转录抑制剂的协同作用下可直接引起小鼠肝细 胞的凋亡. Takei et al[45]证明抗TNF-α抗体可阻止GalN引起的肝细胞凋亡 ，防止暴发性肝衰竭发生. Lang et al[46]研究了TNF-α与肝星形细胞凋亡 的关系，结果表明，TNF-α对已激活的肝星形细胞可产生凋亡诱导，此作用能被TNF-α的主要下游效应物NF-kB所阻断. NF-kB对肝脏再生及炎症反应均有调节作用[47]，它能通过其产生的一组基因产物的协同作用抑制TNF-α诱发的Caspase-8激活来阻止凋 亡[48]，这是一种负反馈机制. 由于在肝纤维化恢复期，激活状态的肝星形细胞减少主要通过凋亡机制而非表型逆转[49]，加强对TNF-α介导的星形细胞凋亡机 制研究将有助于指导未来抗纤维化的治疗策略.
2 白介素
2.1 白介素6 (IL-6) 白介素6(IL-6) 作为一种具有多种生物学功能的细胞因子[50]，在肝脏的生理和病理过程中的作用已引起广大学者的关注[51-53]. 活化的肝星形细胞和肝成纤维细胞是肝脏IL-6的主要来源，LPS, IL-1β, TNF-α均是上述二类细胞合成分泌IL-6的有效刺激物，这已在体外培养人肝脏贮脂细胞和成纤维细胞的实验中得到证实[54]. NF-kB也可通过促进IL-6基因转录进一步扩大炎症反应[55]. 对急、慢性肝病患者的肝脏病理标本以IL-6单克隆抗体行免疫荧光检测发现肝脏病理状态下局部分泌IL-6增多，促进炎症发展和免疫反应[56]. 国内外报道肝炎病毒感染后肝硬变及酒精性肝硬变患者血清 中IL-6含量均高于正常对照组[57,58]，且丙型肝炎病毒感染后肝硬变>酒精性硬变. 国内甄真et al[59]报道同正常对照组相比，病毒性肝炎患者IL-6活性和可溶性白介素6受体(sIL-6R)水平均明显升高，依次为慢性重型肝炎>肝炎后肝硬 变(活动性)>慢性肝炎(重度)>慢性肝炎(中度)>急性黄疸型肝炎>慢性肝炎(轻度)，其中慢性重型肝炎又明显高于其他各组，提示血清IL-6和sIL-6R的升高与肝细胞坏死密切相关. IL-6和IL-1β, TNF-α均为肝实质细胞合成急性相反应蛋白的强力诱导剂[ 60-62]，急性相反应蛋白通过抑制蛋白酶、加强α1(Ⅰ)型前胶原及组 织金属蛋白酶抑制物(TIMP)的转录表达及增强损伤因子的作用维持或加速肝纤维化的进 展[63,64]；IL-6也能直接刺激肝细胞上调TIMP-1的表达[65]. Cressman et al[66]发现IL-6基因敲除小鼠行部分肝切除后，由于肝细胞增殖能力缺陷，导致小鼠肝坏死和肝衰竭，而在手术前单次予定量IL-6注射后，术后小鼠 肝组织能恢复到接近正常水平，提示IL-6是损 伤后促进细胞增殖的重要物质. Natsume et al[67]报道CCl4诱导的IL-6基 因敲除小鼠较正常对照组肝纤维化损害轻，且伴有肝细胞生长因子(HGF)和生长转化因子β1(TGF-β1)的表达下降，故认为肝纤维化早期，IL-6基因表达增强，并通过调节肝内其他细胞因子的表达来参与纤维化进程，其同TNF-α, IL-3, IL-4, IL-5, IL-8等细胞因子均存在协同作用[68,69]. 此外，近来有资料表明IL-6还可能通 过Fas途径调节肝星形细胞的凋亡[70].
2.2 白介素10(IL-10) 引发和促进炎症和纤维化反 应的细胞因子在目前的研究中倍受瞩目，事实上，同其相拮抗的细胞因子也同等重要. IL-10在起抗炎、抗纤维化作用的免疫调节因子中占突出地位[71-73]，主要由TH2细胞，巨噬细胞，肥大细胞[74]，肝细胞[75]及肝星形细胞[76]等产生. 动物模型[25]和细胞培养[77]均证实在肝纤维化时IL-10的表达增高，TNF-α, TGF-β, LPS在体外均能促进活化的星形细胞合成并分泌IL-10，且分泌量随活化的细胞数增多而升高，但当肝纤维化进展到肝硬变时，IL-10的合成量渐下降. IL-10具有复杂而广泛的生物学功能：抑制TH1细胞产生IL-2和INF-γ,发挥抗炎作用[78]； 刺激肥大细胞的增殖和蛋白酶的表达[79]；下调巨 噬细胞的功能表达，包括Π形组织相容性抗原的提呈[80,81]、NO的分泌[82 ]及类花生酸物质的合成[83,84]；抑制单核细胞表达ICAM-1, BT等粘附分子[85]，阻止T细胞、中性粒细胞和肌成纤维细胞合成趋化因子[86,87]； 对许多细胞特别是单核细胞和巨噬细胞，具广泛抑制其合成化学致炎因子的作用[88]；刺激胶原酶，主要是金属蛋白酶Ⅰ(MMP-Ⅰ)的合成并抑制α1(Ⅰ)型胶原的转录合 成[77]，缓解胶原的大量沉积. Thompson et al[89]报道IL-10基因敲除小鼠予CCl4诱导后，血清检测及病理均证实其纤维化病损较正常对照组明显加重，且近来已有IL-10试用于临床治疗肝纤维化的报道[90]. 可见，IL-10通过多种调节机制参与肝纤维化进程，其在炎症因子所致肝纤维化中的抗纤维化作用已较为肯定[91,92].
3 TNF-α, IL-6及IL-10的相互关系各类细胞因子形成一个复杂的网络来调节肝纤维化的发生发展，每个细胞因子不是孤立的发 挥作用，而同其他细胞因子之间存在千丝万缕的联系. 肝纤维化发病中，TNF-α,IL-6及IL-10之间的联系值得关注. 肝病初期，TNF-α通过其主要下游效应物NF-kB活化星形细 胞，自分泌IL-6及IL-10等细胞因子[93-95]，NF-kB还可作用于IL-6基因启动子上的顺式调控序列，从而实现转录和转录后水平的调控[96,97]. IL -6对TNF-α存在微妙的双向调节作用，Mizuhara[98]通过注射刀豆蛋白A建立小 鼠肝细胞损害模型，证明TNF-α是诱导肝损害的主要细胞因子，但在注射刀豆蛋白A前注射一次IL-6可部分抑制TNF-α作用. 这可能是因为IL-6诱导合成急性相反应蛋白中包括 蛋白酶抑制剂，而TNF-α的细胞毒作用部分依赖蛋白酶. IL-6对TNF-α的作用具有时相 性，若在注射刀豆蛋白A后应用IL-6反而加重肝损，这可能同其增加肝TNF-α受体表达有 关. 由于TNF-α在注射刀豆蛋白A早期产生，稍后再予以IL-6不能抑制TNF-α的活性反而通过上调其受体加强TNF-α的细胞毒性作用. Louis et al[99]发现CCl4诱导肝纤维化的C57Bl/6IL-10基因敲除小鼠血清TNF-α和TGF-β1较正常对照组明显升高，病理提示进展性中央小叶炎性浸润及增生反应增强，纤维化病损明显加重；且Wang et al[100]报道IL-10能下调TNF-α下游效应物NF- kB的表达，因此，内源性IL-10可能部分通过调控TNF信号通路来局限细胞增殖和纤维化的进展. 肝纤维化进程中，IL-10通过抑制巨噬细胞释放TNF-α或下调NF-kB减轻炎症反应 ，而IL-6通过上调TNF-α受体等机制加强TNF-α的生物活性，在这个TNF信号环路中，NF-kB是中心环节，抑制NF-kB代表了阻断肝纤维化的重要靶向. 由此可见，深入阐明细胞因子及其网络的相互作用必将为治疗肝纤维化提供更为广阔的前景.
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