修回日期: 2009-07-20
接受日期: 2009-07-21
在线出版日期: 2009-07-28
肝脏炎性损伤的发生发展过程中, 细胞因子起着很重要的作用. 众多致炎细胞因子和抗炎细胞因子构成细胞因子调控网络, 共同作用于组织细胞, 导致肝脏病变的演变. 近年来, 学者们在部分病毒性肝炎、脂肪肝、酒精性肝病、肝硬化等慢性肝脏疾病进行了大量研究, 有不少新发现. 本文简要总结了近年来国内外学者在细胞因子与慢性肝脏疾病关系的研究中所取得的共识与进展, 并试图提出未来研究议题供同行参考.
引文著录: 孙明珠, 党双锁. 细胞因子与慢性肝脏疾病的研究进展. 世界华人消化杂志 2009; 17(21): 2121-2126
Revised: July 20, 2009
Accepted: July 21, 2009
Published online: July 28, 2009
Cytokines play an important role in the development of liver inflammatory injury. Various pro-inflammatory and anti-inflammatory cytokines constitute a cytokine network that mediates the development of various liver diseases. In recent years, numerous studies have been carried out on chronic liver diseases such as viral hepatitis, fatty liver, alcoholic liver disease and hepatic cirrhosis. Here, we will review the recent advances in research on the role of cytokines in chronic liver diseases and discuss future prospects in this field.
- Citation: Sun MZ, Dang SS. Advances in research on the role of cytokines in chronic liver diseases. Shijie Huaren Xiaohua Zazhi 2009; 17(21): 2121-2126
- URL: https://www.wjgnet.com/1009-3079/full/v17/i21/2121.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v17.i21.2121
在研究慢性肝脏疾病肝损伤的发生发展过程中, 随着对细胞因子的认识和发现, 学者们发现众多细胞因子参与肝损伤的发生演变过程. 加深了解细胞因子在肝损伤中的作用对于阐释肝脏疾病的发生机制意义重大.
细胞因子是20世纪50年代在研究感染性疾病时发现的. 1974年Cohen et al提出了细胞因子的概念, 把在细胞间传递信息、对细胞起活化或抑制作用、并可由多种细胞产生的可溶性多肽分子统称为细胞因子[1].
据目前英汉汉英医学分科词典的解释: 细胞因子是由活化的免疫细胞和某些基质细胞分泌的、介导和调节免疫、炎症反应的小分子多肽, 是除免疫球蛋白和补体外的另一类非特异性免疫效应物质. 他包括由淋巴细胞产生的淋巴因子(lymphokine)和由单核/巨噬细胞产生的单核因子(monokine)等.
根据细胞因子在炎症反应中的不同作用分为: 促炎细胞因子和抗炎细胞因子. 促炎细胞因子, 也称致炎因子, 包括肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、白介素(interleukin, IL, 包括IL-1、IL-6、IL-8、IL-12等)、干扰素-γ(interferon-γ, IFN-γ)、集落刺激因子(colony stimulating factor, CSF)等, 与炎症的发生发展密切相关. 抗炎细胞因子, 也称抗炎因子, 包括IL-2、IL-4、IL-10、IL-13、脂连素(adiponectin)、转化生长因子-β(transforming growth factor-β, TGF-β)、IL-1受体抗体(interleukin-1 receptor antagonist, IL-1ra)等[2-6].
慢性乙型肝炎是细胞介导的免疫反应异常的结果. 有学者[17]曾检测慢性乙型肝炎患者100例及正常人15例血清TNF-α、IL-2、IL-6、IL-8及HBV DNA定量等项指标, 结果与正常人比较, 轻度、中度、重度慢性乙型肝炎患者血清致炎因子TNF-α、IL-6、IL-8、抗炎因子IL-2含量均有不同程度升高, 其升高情况为: 慢性乙型肝炎重度>中度>轻度. 慢性乙型肝炎各组HBV DNA水平无明显变化. HBV DNA复制水平与血清致炎因子TNF-α和IL-6、抗炎因子IL-2水平呈正相关. 随着病程的延长, 血清致炎因子TNF-α、IL-6、IL-8、抗炎因子IL-2水平逐渐升高. 由此得出结论: 慢性乙型肝炎患者血清致炎因子TNF-α、IL-6和IL-8、抗炎因子IL-2水平的高低能够反映肝细胞损害的程度. 这些细胞因子参与了乙型肝炎的发病过程, 在乙型肝炎转为慢性化过程中, 均不同程度发挥了作用.
内毒素介导的细胞因子释放在脂肪肝的发展中占重要地位. 脂肪肝患者肠道革兰阴性菌增加, 肠壁通透性增加, 网状内皮的功能降低, 从而使血清中的内毒素增加. 内毒素可以激活Kupffer细胞, 使其释放细胞因子, 造成肝脏的损害. 经测定脂肪肝患者血清中致炎因子TNF-α、IL-6水平升高. 给予抗TNF-α抗体可减少脂肪肝的发生, 可见TNF-α、IL-6参与酒精性脂肪肝的形成发展. 有学者研究发现TNF-α与丙二醛正相关, 与超氧化物歧化酶(super oxide dismutase, SOD)负相关, 认为TNF-α参与肝细胞的损害且与肝内过氧化反应加强、抗过氧化反应能力削弱有关[18-20].
肝硬化的病情发展, 大多数经历了从代偿期到失代偿期的过程. 为了评估酒精性肝硬化进展中细胞因子的作用, 有学者[21-25]评估了代偿和失代偿性酒精性肝硬化患者血清中致炎因子TNF-α、IL-6、 IL-8, 抗炎因子IL-2、IL-10、TGF-β水平. 代偿性酒精性肝硬化的特征是IL-6增加、IL-10减少; TNF-α、IL-8、TGF-β水平与对照组的相同. 在失代偿性酒精性肝硬化患者血清中, 除了IL-6增加, 也检测到TNF-α和IL-8增加了; TGF-β和IL-10水平与对照组的相同. 这些结果有力地说明: 代偿、尤其是失代偿酒精性肝硬化的特征是致炎因子和抗炎因子之间显著的平衡紊乱.
酒精性肝炎是一个典型的致炎因子TNF-α相关性疾病[26]. Mookerjee et al最近证明: TNF-α在酒精性肝炎肝门和全身血流动力紊乱中发挥主要作用[27]. TNF-α的变化是肝脏损伤最早发生的活动之一, 他刺激其他细胞因子的产生. 酒精性肝硬化时TNF-α似乎可能作为患者肝移植时肝功能紊乱的另外一个诊断标志. 而且, 一些研究数据显示: 酒精性肝硬化不仅与致炎因子增多有关, 而且与致炎因子和抗炎因子之间显著的平衡紊乱有关. 而TNF-α的紊乱可能与慢性乙型肝炎的死亡率有关. 实际上, 对缺少1型TNF受体的小鼠的抗体中和研究和实验显示: 在部分肝切除术后, 肝脏的再生是由TNF-α1型TNF受体的活化开始的. 动物实验数据进一步证实了TNF-α在酒精相关性肝脏疾病中发挥主要作用. 支持TNF-α作用的最引人注目的证据来自于对小鼠的研究, 在一项研究中发现, 小鼠对酒精导致的肝脏疾病产生免疫耐受的时候, 1型TNF受体基因就会断裂[28-30].
在以上研究慢性肝脏疾病与细胞因子关系的过程中, 我们不难发现体内各细胞因子间相互作用, 形成细胞因子作用网络. 细胞因子间的生物学活性通常存在交叉现象, 即几种不同的细胞因子具有相同的生物学活性. 一种细胞因子通常影响其他细胞因子的合成, 导致连锁反应. 例如, 在炎症反应的急性期, 致炎因子TNF-α诱导致炎因子IL-1的合成, 后者又诱导致炎因子IL-6的合成. 细胞因子的生物作用可相互影响, 两种细胞因子可能产生拮抗作用, 亦可能产生累加效应或协同作用. 细胞因子之间的相互诱导、抑制或加强最终形成多向调节网络, 这对免疫反应及炎症反应有重要的调控意义.
致炎因子IL-1和TNF-α是炎症的主要中间介质, 具有相同的活性, 在肝组织纤维化过程中, 他们能够激活几种蛋白激酶; 而在肝细胞的体外培养中, 能由IL-1激活的酶谱范围更广, 提示在肝细胞增殖过程中IL-1通过更多的通路来起作用. 致炎因子IL-6是多种细胞如单核吞噬细胞、血管内皮细胞、成纤维细胞和激活的T淋巴细胞等对IL-1和TNF-α反应的产物. IL-6主要作用于肝细胞和B淋巴细胞, 刺激肝细胞合成纤维蛋白原等几种血清蛋白, 是活化的B淋巴细胞分化晚期的主要刺激因子. TNF-α、IL-1和IL-6协同介导炎症的急性期反应. 在急性期反应中, 这些炎症因子刺激肝细胞合成包括C-反应蛋白、a2-巨球蛋白等抗蛋白酶和纤维蛋白酶原在内的所谓急性期反应蛋白, 抑制肝细胞合成白蛋白及转铁蛋白[31-33].
目前发现的致炎因子CSF有粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage-colony stimulating factor, GM-CSF)、单核-巨噬细胞集落刺激因子(monocyte-colony stimulating factor, M-CSF)、粒细胞集落刺激因子(granulocyte-colony stimulating factor, G-CSF). M-CSF是炎症反应的敏感指标: 在炎症反应中炎性细胞浸润激活而产生M-CSF, M-CSF又可通过其受体引起内皮细胞、单核-巨噬细胞释放更多的M-CSF. 研究发现, 急性炎症患者循环血中M-CSF较正常对照组显著增高, 因此M-CSF的高低与炎症反应程度密切相关, 炎症反应越重, M-CSF升高越明显. M-CSF可以促进单核细胞释放致炎因子, 是体内重要的致炎因子之一, 而IL-10则是体内重要的抗炎因子, 能拮抗M-CSF的致炎作用. 肝移植后用G-CSF动员自体骨髓干细胞, 受体生存率高, 移植肝再生明显, 肝损伤轻[34-37].
抗炎因子TGF-β具有较强的抑制肝细胞有丝分裂的作用, 所以他在肝细胞再生过程中起着重要的调节作用. TGF-β可抑制肝细胞生长因子(hepatocyte growth factor, HGF)、TGF-α和表皮生长因子(epidermal growth factor, EGF)等对肝细胞再生的刺激作用. TGF-β是肝纤维化的重要始动因子, 由于在肝脏严重损伤时血浆浓度可显著升高, 并与谷丙转氨酶(alanine transaminase, ALT)和谷草转氨酶(aspartate transaminase, AST)水平密切相关, 因此TGF-β是肝脏炎症坏死的标志物[38-39].
大多数慢性肝脏疾病的特征是: 许多致炎因子和抗炎因子在肝脏中过度表达所造成的炎症过程. 致炎因子和抗炎因子是肝脏炎症疾病的驱动力, 这往往导致肝脏纤维化和肝硬化. 致炎因子TNF-α、抗炎因子IL-10和脂联素已经成为研究许多慢性肝脏疾病的重要因素和评价指标.
虽然之前在法国完成的一项研究显示了抗TNF-α药物对治疗酒精性肝炎有潜在的有害作用, 但是人们仍然进行试验性研究, 如研究像英夫利昔单抗(infliximab)和依那西普(etanercept)这样的抗TNF-α药物对于酒精性肝炎的治疗作用[40-43]. 在一项24 wk皮下使用依那西普的试验中, 抗TNF-α药物使丙型肝炎好转[44-45].
抗TNF抗体治疗也成功地用于预防酒精引起的老鼠肝脏损伤[46-51]. 有一个假说: 内毒素类肠内细菌产物可能在肝脏Kupffer细胞和其他细胞的活化中发挥重要的作用. 这个假说与最近的一项观察相一致: 长期摄入酒精的野生型老鼠产生的肝脏损伤比敲除分化簇14(cluster of differentiation14, CD14)引起的肝脏损伤更严重[52-53]. 这些结果进一步支持了这样一个观点: 通过细胞内受体CD14发挥作用的肠内毒素在酒精导致的肝脏损伤早期发挥重要的作用. 有研究表明: 抗TNF-α治疗(TNF-α中和治疗)可以促进多种因素(酒精性、病毒性)所致的肝脏损伤的恢复[26]. 可能不久的将来使用依那西普抗TNF的治疗措施会成为一种优先选择的治疗措施. TNF-α中和疗法在许多慢性炎症疾病中已经被证明为高度有效. 虽然评估抗TNF-α疗法的研究产生了许多有争议的结论, 一些实验数据从总体而言仍然证明抗TNF-α治疗是最有吸引力的治疗方法.
IL-10是一种重要的抗炎因子, 可抑制免疫细胞的活化, 具有潜在的抗炎和抗纤维化作用. 像IL-10的抗炎因子已经在慢性肝脏疾病患者身上试验过. IL-10产生减少可能与酒精性肝病的病理机制相关. 据检测, 在肝星形细胞中IL-10可能以自分泌的方式抑制胶原的合成, 而肝星形细胞参与了肝脏纤维化的重塑过程. 与野生小鼠相比, IL-10基因敲除的小鼠在重复注射四氯化碳后更多的出现了早期肝纤维化. 然而, 从早期肝纤维化小鼠中分离出来的肝星形细胞显示IL-10的合成有缺陷. 这一缺陷可能成为病理性胶原产生过剩和从肝病到肝硬化进展的基础[54-60]. 在肝硬化进展中, IL-10的作用尤其应当加以阐释.
脂联素是近来发现的一种脂肪组织特异性抗炎因子. 脂联素可通过cAMP-PKA依赖途径抑制TNF-α诱导的人主动脉内皮细胞黏附分子的表达, 脂联素通过PI3K/Akt信号途径的激活, 降低NF-κB结合活性, 刺激体外培养的人巨噬细胞分泌IL-10和IL-1ra, 从而发挥抗炎作用. 并可明显降低肝细胞的凋亡率, 从而起到保护肝细胞的作用[61-64]. 预先应用重组脂联素干预可降低ALT血清水平以及致炎因子IL-4、TNF-α和IFN-γ的血清水平, 以及升高抗炎因子IL-10的血清水平及其在肝脏中的表达, 即脂联素通过促进抗炎因子、抑制致炎因子的产生, 减轻肝脏炎症损伤[65-71]. 脂联素在慢性肝脏疾病的表达和作用及与炎症的关系越来越受到广大学者的关注, 但目前研究结果不尽相同, 甚至相互矛盾, 需要进一步的研究与验证.
细胞因子的失衡是慢性肝脏疾病进程中的基本环节, 细胞因子与慢性肝脏疾病之间的相互作用会给未来的临床提供一个很有吸引力的诊断依据和治疗思路. 事实上, 在指导性研究中, 抗炎症因子治疗很可能最终获得成功. 在不久的将来, 致炎因子抵抗会成为基本的临床概念, 有希望产生更好的治疗许多慢性肝脏疾病的方法. 虽然当前的研究已经阐明一些关键的细胞因子在慢性肝脏疾病中的作用, 但是目前尚未有对慢性肝脏疾病的不同状态下致炎因子与抗炎因子变化的研究, 更没有对慢性肝脏疾病不同组别的人群致炎因子和抗炎因子的变化进行研究, 也没有对这些相关的致炎因子和抗炎因子之间的相互关系进行研究, 而慢性肝脏疾病中这些细胞因子的变化, 及其相互关系, 可以揭示慢性肝脏疾病的感染状态、揭示慢性肝脏疾病的预后, 为慢性肝脏疾病的早期诊断、及时治疗提供依据. 只有在整个机体的内环境中弄清炎症因子之间的相互作用的具体机制, 才有可能进一步阐释肝脏疾病的发生行为, 并为临床治疗一系列慢性肝脏疾病寻找出高效、安全的途径.
在学者发现并提出细胞因子的概念以后, 人们就开始对细胞因子在病毒性肝炎、脂肪肝、酒精性肝病、肝硬化等相关慢性肝脏疾病进行大量的研究. 发现各种原因引起肝脏炎性损伤的发生发展过程中, 细胞因子起着很重要的作用. 众多的致炎细胞因子和抗炎细胞因子构成细胞因子调控网络,共同作用于组织细胞, 导致肝脏病变程度的演变与走向.
赵桂鸣, 主任医师, 天津市肝病研究所天津市传染病医院慢性肝炎科.
细胞因子作为炎症反应的重要载体与肝脏疾病的进展或演变密切相关, 由于细胞因子网络调控的复杂性, 目前系统规范的研究不够深入. 对细胞因子在酒精性肝病的作用中发现细胞因子起着重要作用, 提示探索在其他慢性肝脏疾病发展变化中研究细胞因子的作用意义重大.
Louis et al报道TNF-α、白介素、干扰素、TGF-β等细胞因子与肝脏疾病相关; Mookerjee et al报道TNF-α在酒精性肝炎肝门和全身血流动力紊乱中发挥主要作用.
本文较全面地总结了近年来国内外学者在细胞因子与慢性肝脏疾病之间的关系, 提出系统动态地研究细胞因子在慢性肝脏疾病发生发展过程中意义重大.
本文通过介绍细胞因子在慢性肝脏疾病中的研究结果, 提出细胞因子之间的网络调控是影响慢性肝脏疾病进程的重要因素, 对其某个细胞因子的检测或干预可能对于判断病情及治疗均有重要的意义.
1 细胞因子: 细胞因子是由活化的免疫细胞和某些基质细胞分泌的、介导和调节免疫、炎症反应的小分子多肽,是除免疫球蛋白和补体外的另一类非特异性免疫效应物质. 他包括由淋巴细胞产生的淋巴因子(lymphokine)和由单核/巨噬细胞产生的单核因子(monokine)等.
2 脂联素: 为30 kDa的脂肪细胞补体相关蛋白, 肝脏和肌肉中存在脂联素受体, 刺激肝脏脂联素受体可激活AMPK和PPAR-α, 起抗肝脂肪贮积作用. 脂联素还具有抑制NF-κB活化及抑制巨噬细胞功能的抗炎作用. 脂联素和TNF-α对IR和炎症的影响作用正好相反.
本文描述条理清楚, 结构严谨, 依据充分, 参考文献引用合理, 内容重要, 为研究细胞因子在慢性肝脏疾病中的作用提供了有力的依据.
编辑:李军亮 电编:吴鹏朕
| 1. | Cohen S, Bigazzi PE, Yoshida T. Commentary. Similarities of T cell function in cell-mediated immunity and antibody production. Cell Immunol. 1974;12:150-159. [PubMed] [DOI] |
| 2. | Khairova RA, Machado-Vieira R, Du J, Manji HK. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2009;12:561-578. [PubMed] [DOI] |
| 3. | Kim EY, Moudgil KD. Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunol Lett. 2008;120:1-5. [PubMed] [DOI] |
| 4. | Uçeyler N, Sommer C. [Cytokine regulation and pain. Results of experimental and clinical research]. Schmerz. 2008;22:652-664. [PubMed] [DOI] |
| 5. | Godukhin OV. [The role of cytokines in the seizure activity development in the brain]. Zh Vyssh Nerv Deiat Im I P Pavlova. 2007;57:541-552. [PubMed] |
| 6. | Niemann CU, Xu F, Choi S, Behrends M, Park Y, Hirose R, Maher JJ. Short Passive Cooling Protects Rats During Hepatectomy by Inducing Heat Shock Proteins and Limiting the Induction of Pro-Inflammatory Cytokines. J Surg Res. 2008; Oct 16. [Epub ahead of print]. [PubMed] |
| 7. | Louis R, Shute J, Goldring K, Perks B, Lau LC, Radermecker M, Djukanovic R. The effect of processing on inflammatory markers in induced sputum. Eur Respir J. 1999;13:660-667. [PubMed] [DOI] |
| 8. | Stewart CR, Landseadel JP, Gurka MJ, Fairchild KD. Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice*. Pediatr Crit Care Med. 2009; Jul 11. [Epub ahead of print]. [PubMed] |
| 9. | Barkhausen T, Hildebrand F, Krettek C, van Griensven M. DHEA-dependent and organ-specific regulation of TNF-alpha mRNA expression in a murine polymicrobial sepsis and trauma model. Crit Care. 2009;13:R114. [PubMed] [DOI] |
| 10. | Jiang L, Jiang LS, Cheng NS, Yan LN. Current prophylactic strategies against hepatitis B virus recurrence after liver transplantation. World J Gastroenterol. 2009;15:2489-2499. [PubMed] [DOI] |
| 11. | Matsuzaki K. Modulation of TGF-beta signaling during progression of chronic liver diseases. Front Biosci. 2009;14:2923-2934. [PubMed] [DOI] |
| 12. | Wilt TJ, Shamliyan T, Shaukat A, Taylor BC, MacDonald R, Yuan JM, Johnson JR, Tacklind J, Rutks I, Kane RL. Management of chronic hepatitis B. Evid Rep Technol Assess (Full Rep). 2008;1-671. [PubMed] |
| 13. | Ludwiczek O, Vannier E, Moschen A, Salazar-Montes A, Borggraefe I, Gabay C, Enrich B, Kaser A, Siegmund B, Dinarello C. Impaired counter-regulation of interleukin-1 by the soluble IL-1 receptor type II in patients with chronic liver disease. Scand J Gastroenterol. 2008;43:1360-1365. [PubMed] [DOI] |
| 14. | Lai WK, Curbishley SM, Goddard S, Alabraba E, Shaw J, Youster J, McKeating J, Adams DH. Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function. J Hepatol. 2007;47:338-347. [PubMed] [DOI] |
| 15. | Carroll MB, Bond MI. Use of tumor necrosis factor-alpha inhibitors in patients with chronic hepatitis B infection. Semin Arthritis Rheum. 2008;38:208-217. [PubMed] [DOI] |
| 16. | Hosseini-Moghaddam SM, Mousavi A, Alavian SM. Is {beta}-interferon a promising therapeutic option for the management of hepatitis C? J Antimicrob Chemother. 2009;63:1097-1103. [PubMed] [DOI] |
| 17. | Tilg H, Kaser A, Moschen AR. How to modulate inflammatory cytokines in liver diseases. Liver Int. 2006;26:1029-1039. [PubMed] [DOI] |
| 19. | Tordjman J, Guerre-Millo M, Clément K. Adipose tissue inflammation and liver pathology in human obesity. Diabetes Metab. 2008;34:658-663. [PubMed] [DOI] |
| 20. | Purohit V, Gao B, Song BJ. Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res. 2009;33:191-205. [PubMed] [DOI] |
| 21. | Daniluk J, Szuster-Ciesielska A, Drabko J, Kandefer-Szerszeń M. Serum cytokine levels in alcohol-related liver cirrhosis. Alcohol. 2001;23:29-34. [PubMed] [DOI] |
| 22. | Dang SS, Wang BF, Cheng YA, Song P, Liu ZG, Li ZF. Inhibitory effects of saikosaponin-d on CCl4-induced hepatic fibrogenesis in rats. World J Gastroenterol. 2007;13:557-563. [PubMed] |
| 23. | Holt AP, Salmon M, Buckley CD, Adams DH. Immune interactions in hepatic fibrosis. Clin Liver Dis. 2008;12:861-882, x. [PubMed] [DOI] |
| 24. | Moreno M, Bataller R. Cytokines and renin-angiotensin system signaling in hepatic fibrosis. Clin Liver Dis. 2008;12:825-852, ix. [PubMed] [DOI] |
| 25. | Svegliati-Baroni G, De Minicis S, Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int. 2008;28:1052-1064. [PubMed] |
| 26. | Menon KV, Stadheim L, Kamath PS, Wiesner RH, Gores GJ, Peine CJ, Shah V. A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis. Am J Gastroenterol. 2004;99:255-260. [PubMed] [DOI] |
| 27. | Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R, Jalan R. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. Gut. 2003;52:1182-1187. [PubMed] [DOI] |
| 28. | Laso FJ, Vaquero JM, Almeida J, Marcos M, Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells. Alcohol Clin Exp Res. 2007;31:846-854. [PubMed] [DOI] |
| 29. | Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology. 1997;26:1530-1537. [PubMed] [DOI] |
| 30. | Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117:942-952. [PubMed] [DOI] |
| 31. | Pajak B, Orzechowska S, Pijet B, Pijet M, Pogorzelska A, Gajkowska B, Orzechowski A. Crossroads of cytokine signaling--the chase to stop muscle cachexia. J Physiol Pharmacol. 2008;59 Suppl 9:251-264. [PubMed] |
| 32. | Tuttolomondo A, Di Raimondo D, di Sciacca R, Pinto A, Licata G. Inflammatory cytokines in acute ischemic stroke. Curr Pharm Des. 2008;14:3574-3589. [PubMed] [DOI] |
| 33. | Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem. 2008;49:133-143. [PubMed] [DOI] |
| 34. | 王 君平, 孙 殿兴, 李 兵顺, 李 敏然, 郭 争荣, 亢 继文, 李 伟勇. 粒细胞集落刺激因子防治小鼠CCl4所致肝损伤的作用. 世界华人消化杂志. 2007;15:3395-3402. [DOI] |
| 35. | Koskinas J, Zacharakis G, Sidiropoulos J, Elefsiniotis J, Savvas S, Kotsiou S, Kountouras D, Schina M, Kostopoulos P, Archimandritis A. Granulocyte colony stimulating factor in HCV genotype-1 patients who develop Peg-IFN-alpha2b related severe neutropenia: a preliminary report on treatment, safety and efficacy. J Med Virol. 2009;81:848-852. [PubMed] [DOI] |
| 36. | Han Y, Yan L, Han G, Zhou X, Hong L, Yin Z, Zhang X, Wang S, Wang J, Sun A. Controlled trials in hepatitis B virus-related decompensate liver cirrhosis: peripheral blood monocyte transplant versus granulocyte-colony-stimulating factor mobilization therapy. Cytotherapy. 2008;10:390-396. [PubMed] [DOI] |
| 37. | Durante-Mangoni E, Iardino P, Utili R, Adinolfi LE, Ruggiero G. Defective synthesis of granulocyte-colony stimulating factor in pegylated interferon-alpha treated chronic hepatitis C patients with declining leukocyte counts. Antivir Ther. 2006;11:637-640. [PubMed] |
| 38. | Jung YA, Lee KM, Kim MK, Jung GS, Seo YJ, Kim HS, Cho HC, Lee KU, Park KG, Lee IK. Forkhead transcription factor FoxO1 inhibits insulin- and transforming growth factor-beta-stimulated plasminogen activator inhibitor-1 expression. Biochem Biophys Res Commun. 2009;386:757-761. [PubMed] [DOI] |
| 39. | Liang TJ, Yuan JH, Tan YR, Ren WH, Han GQ, Zhang J, Wang LC, Qin CY. Effect of ursodeoxycholic acid on TGF beta1/Smad signaling pathway in rat hepatic stellate cells. Chin Med J (Engl). 2009;122:1209-1213. [PubMed] |
| 40. | Williams R. The pervading influence of alcoholic liver disease in hepatology. Alcohol Alcohol. 2008;43:393-397. [PubMed] [DOI] |
| 41. | Koca SS, Bahcecioglu IH, Poyrazoglu OK, Ozercan IH, Sahin K, Ustundag B. The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet. Inflammation. 2008;31:91-98. [PubMed] [DOI] |
| 42. | Mora JM, Olmedo R, Curiel E, Muñoz J, Herrera M, Séller G. [MARS (Molecular Absorbent Recirculating System) as hepatic extracorporeal care in serious acute liver failure of alcoholic etiology]. Med Intensiva. 2006;30:402-406. [PubMed] [DOI] |
| 43. | Song Z, Deaciuc I, Song M, Lee DY, Liu Y, Ji X, McClain C. Silymarin protects against acute ethanol-induced hepatotoxicity in mice. Alcohol Clin Exp Res. 2006;30:407-413. [PubMed] [DOI] |
| 44. | Torre F, Rossol S, Pelli N, Basso M, Delfino A, Picciotto A. Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin. Clin Exp Immunol. 2004;136:507-512. [PubMed] [DOI] |
| 45. | Giannitti C, Benucci M, Caporali R, Manganelli S, Bellisai F, Sebastiani GD, Galeazzi M. Efficacy and safety of anti-TNF-alpha therapy combined with cyclosporine A in patients with rheumatoid arthritis and concomitant hepatitis C virus infection. Int J Immunopathol Pharmacol. 2009;22:543-546. [PubMed] |
| 46. | Jing Y, Shishkov A, Ponnappa BC. Inhibition of tumor necrosis factor alpha secretion in rat Kupffer cells by siRNA: in vivo efficacy of siRNA-liposomes. Biochim Biophys Acta. 2008;1780:34-40. [PubMed] |
| 47. | Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:24-34. [PubMed] [DOI] |
| 48. | Granado M, Priego T, Martín AI, Vara E, López-Calderón A, Angeles Villanúa M. Anti-tumor necrosis factor agent PEG-sTNFRI improves the growth hormone/insulin-like growth factor-I system in adjuvant-induced arthritic rats. Eur J Pharmacol. 2006;536:204-210. [PubMed] [DOI] |
| 49. | Ponnappa BC, Israel Y, Aini M, Zhou F, Russ R, Cao QN, Hu Y, Rubin R. Inhibition of tumor necrosis factor alpha secretion and prevention of liver injury in ethanol-fed rats by antisense oligonucleotides. Biochem Pharmacol. 2005;69:569-577. [PubMed] [DOI] |
| 50. | Levitsky J, Mailliard ME. Diagnosis and therapy of alcoholic liver disease. Semin Liver Dis. 2004;24:233-247. [PubMed] [DOI] |
| 51. | Diehl AM. Effect of ethanol on tumor necrosis factor signaling during liver regeneration. Clin Biochem. 1999;32:571-578. [PubMed] [DOI] |
| 52. | Spahr L, Rubbia-Brandt L, Frossard JL, Giostra E, Rougemont AL, Pugin J, Fischer M, Egger H, Hadengue A. Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study. J Hepatol. 2002;37:448-455. [PubMed] [DOI] |
| 53. | Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG. Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol. 2001;166:4737-4742. [PubMed] |
| 54. | Mosmann TR. Properties and functions of interleukin-10. Adv Immunol. 1994;56:1-26. [PubMed] [DOI] |
| 55. | Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263-274. [PubMed] [DOI] |
| 56. | Bouzgarrou N, Hassen E, Farhat K, Bahri O, Gabbouj S, Maamouri N, Ben Mami N, Saffar H, Trabelsi A, Triki H. Combined analysis of interferon-gamma and interleukin-10 gene polymorphisms and chronic hepatitis C severity. Hum Immunol. 2009;70:230-236. [PubMed] [DOI] |
| 57. | Chuang JY, Yang SS, Lu YT, Hsieh YY, Chen CY, Chang SC, Chang CS, Yeh HZ, Kao JH. IL-10 promoter gene polymorphisms and sustained response to combination therapy in Taiwanese chronic hepatitis C patients. Dig Liver Dis. 2009;41:424-430. [PubMed] [DOI] |
| 58. | Emam EA, Emam M, Shehata AE, Emara M. Impact of Schistosoma mansoni co-infection on serum profile of interferon-gamma, interleukin-4 and interleukin-10 in patients with chronic hepatitis C virus infection. Egypt J Immunol. 2006;13:33-40. [PubMed] |
| 59. | Kaplan DE, Ikeda F, Li Y, Nakamoto N, Ganesan S, Valiga ME, Nunes FA, Rajender Reddy K, Chang KM. Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis. J Hepatol. 2008;48:903-913. [PubMed] [DOI] |
| 60. | Verma V, Chakravarti A, Kar P. Cytokine levels of TGF-beta, IL-10, and sTNFalphaRII in type C chronic liver disease. Dig Dis Sci. 2008;53:2233-2237. [PubMed] [DOI] |
| 61. | Derbala M, Rizk N, Al-Kaabi S, Amer A, Shebl F, Al Marri A, Aigha I, Alyaesi D, Mohamed H, Aman H. Adiponectin changes in HCV-Genotype 4: relation to liver histology and response to treatment. J Viral Hepat. 2009; Mar 25. [Epub ahead of print]. [PubMed] |
| 62. | Arvaniti VA, Thomopoulos KC, Tsamandas A, Makri M, Psyrogiannis A, Vafiadis G, Asimakopoulos S, Labropoulou-Karatza C. Serum adiponectin levels in different types of non alcoholic liver disease. Correlation with steatosis, necroinflammation and fibrosis. Acta Gastroenterol Belg. 2008;71:355-360. [PubMed] |
| 63. | Chen X, Sebastian BM, Tang H, McMullen MM, Axhemi A, Jacobsen DW, Nagy LE. Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology. 2009;49:1554-1562. [PubMed] [DOI] |
| 65. | Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112:91-100. [PubMed] |
| 66. | Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, Nihoyannopoulos P. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100:793-798. [PubMed] |
| 67. | Ikejima K, Okumura K, Kon K, Takei Y, Sato N. Role of adipocytokines in hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22 Suppl 1:S87-S92. [PubMed] [DOI] |
| 68. | Siagris D, Vafiadis G, Michalaki M, Lekkou A, Starakis I, Makri M, Margaritis V, Christofidou M, Tsamandas AC, Labropoulou-Karatza C. Serum adiponectin in chronic hepatitis C and B. J Viral Hepat. 2007;14:577-583. [PubMed] [DOI] |
| 69. | Hui CK, Zhang HY, Lee NP, Chan W, Yueng YH, Leung KW, Lu L, Leung N, Lo CM, Fan ST. Serum adiponectin is increased in advancing liver fibrosis and declines with reduction in fibrosis in chronic hepatitis B. J Hepatol. 2007;47:191-202. [PubMed] [DOI] |
| 70. | Liew PL, Lee WJ, Lee YC, Wang HH, Wang W, Lin YC. Hepatic histopathology of morbid obesity: concurrence of other forms of chronic liver disease. Obes Surg. 2006;16:1584-1593. [PubMed] [DOI] |
| 71. | Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol. 2006;101:2629-2640. [PubMed] |