- 移动端
武汉华美生物工程有限公司CUSABIO®品牌商
14 年
手机商铺
- NaN
- 0
- 0
- 2
- 2
公司新闻/正文
炎症“核心三角”的深度对话：IL-6、IL-1β与TNF-α如何共舞，推动疾病进展？
194 人阅读发布时间：2025-11-10 13:18
炎症是机体维持稳态与应对损伤的关键防御机制，但其调控失衡则成为多种慢性疾病的重要病理基础。白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）被广泛认为是炎症反应的核心促炎细胞因子，构成免疫网络的关键枢纽。
深入理解IL-6、IL-1β与TNF-α的分子网络，对于精准诊断及开发多靶点炎症治疗策略具有重要意义。本文旨在阐明三种细胞因子在炎症反应中的分子机制及其病理生理意义，探讨三者在不同疾病中的协同作用与动态平衡，以期为您的研究提供帮助。
1. 什么是核心促炎细胞因子？
炎症是机体抵御感染、修复组织及维持稳态的重要生理过程。该反应通过复杂的细胞与分子事件清除有害刺激并促进组织修复。然而，若炎症反应持续或调控失衡，便会转化为慢性炎症，诱发代谢紊乱、自身免疫病、神经退行性疾病及肿瘤等多种病理状态。研究表明，细胞因子网络在炎症反应中起核心调控作用，其中IL-6、IL-1β和TNF-α是关键的促炎信号介质 [1]。
这些细胞因子由巨噬细胞、T细胞、B细胞及成纤维细胞等多种免疫细胞分泌，通过与特异受体结合激活下游信号通路，从而调节免疫反应与细胞存活。免疫网络分析显示，IL-6、IL-1β和TNF-α在拓扑结构中具有最高中心性，是维持免疫系统稳态的重要节点 [2]。它们的异常激活与糖尿病视网膜病变（DR）、系统性红斑狼疮（SLE）和结直肠癌（CRC）等疾病密切相关 [3-6]。
2. IL-6、IL-1β与TNF-α的信号通路与调控
IL-6、IL-1β与TNF-α是炎症反应的三大核心介质。它们通过特异受体启动信号级联，激活转录因子，调控多种促炎基因表达，从而驱动炎症过程。本章将系统分析三者的信号转导机制、相互调控与分子网络。
2.1 IL-6信号传导与效应
IL-6信号主要通过JAK/STAT3通路实现。IL-6与膜结合或可溶性IL-6受体（IL-6R）结合后，与gp130形成复合体，诱导gp130二聚化并激活JAK家族激酶。随后STAT3被磷酸化、二聚化并转位入核，调控急性期蛋白及炎症相关基因表达 [8]。
IL-6的反式信号（trans-signaling）在炎症调控中尤为关键。例如，IL-6/sIL-6R复合体能激活缺乏膜型IL-6R的细胞，增强破骨细胞分化与炎症反应 [9,10]。在中枢神经系统中，IL-6/sIL-6R可与TNF-α或IL-1β协同，诱导星形胶质细胞IL-6自分泌表达 [11]。此外，miR-223-3p通过负向调控STAT3形成反馈回路，而TNF-α可上调该miRNA以平衡炎症 [12,13]。
在肿瘤中，IL-6/STAT3轴异常激活促进癌细胞增殖与转移，如前列腺癌及肺癌中均观察到STAT3持续磷酸化 [8,15]。病毒因子如KSHV编码的vIL-6亦可激活宿主STAT3通路，提示该信号轴在感染性肿瘤中的重要作用 [16]。
2.2 IL-1β信号传导与效应
IL-1β以无活性的pro-IL-1β形式存在，其成熟依赖NLRP3炎性体介导的Caspase-1激活。炎性体由NLRP3、ASC和Caspase-1组成，能感知LPS、ATP及病毒等刺激，促使IL-1β与IL-18成熟释放 [17-20]。
成熟的IL-1β与IL-1R结合后，启动MyD88依赖性通路，激活IRAKs与TRAF6，进而触发NF-κB与MAPK通路，诱导TNF-α、IL-6等促炎基因转录 [21-24]。
在骨关节炎、肠炎及脓毒症心肌病等疾病中，IL-1β驱动软骨细胞凋亡、基质降解与心肌功能障碍 [19][25][27]。其调控网络涉及多种非编码RNA：如miR-4701-5p通过抑制HMGA1缓解炎症，lncRNA HAGLR沉默则通过miR-130a-3p/JAK1轴减轻软骨细胞损伤 [26][27]。
天然产物（如大蒜多糖）可通过抑制NF-κB/STAT3活化显著降低IL-1β、IL-6与TNF-α水平 [14]。这些研究揭示IL-1β在炎症级联反应中的核心驱动力与多层调控机制。
2.3 TNF-α信号传导与效应
TNF-α通过TNFR1和TNFR2受体介导信号转导，广泛调控细胞存活、凋亡及炎症反应。其主要通路包括NF-κB和MAPK激活级联 [29-32]。TNFR1活化后募集TRADD、RIP1与TRAF2，形成信号复合物并激活IKK复合体。IKKβ磷酸化IκBα后促使其降解，NF-κB二聚体（p65/p50）转位入核并诱导IL-6、IL-1β、CCL2等基因表达 [30][22]。同时，TNF-α还通过p38和JNK调节炎症、凋亡与应激反应 [24][30]。
在类风湿关节炎（RA）中，TNF-α激活滑膜细胞NF-κB/MAPK信号，促进MMPs与IL-6释放，驱动关节破坏 [30]；在动脉粥样硬化中，TNF-α与MCP-1共同参与早期斑块形成 [34]。此外，其与IFN-γ可协同诱导CXCL10⁺炎性巨噬细胞表型，揭示不同炎症疾病间共享的病理机制 [33]。在椎间盘退变与异种移植模型中，TNF-α的持续激活同样导致组织损伤与排斥反应 [17][22]。综上，TNF-α通过NF-κB与MAPK双通路构成炎症反应的核心调控轴。
2.4 细胞因子信号通路整合分析
IL-6、IL-1β与TNF-α下游信号具有显著交叉性。IL-1β和TNF-α通过NF-κB/MAPK驱动炎症扩散，而IL-6以JAK/STAT3为主轴维持反应持续。天然化合物Ebosin及植物醇通过抑制IKKβ、p38与JNK磷酸化有效降低炎症反应 [20][28]。这种信号交叉使炎症反应具备可塑性，也为多靶点干预提供理论依据。
2.5 细胞因子间的交叉与网络调控
IL-6、IL-1β与TNF-α间的相互诱导与反馈调节构建了复杂炎症网络。
研究表明，IL-1β与TNF-α相互诱导并协同促进IL-6表达，形成炎症放大回路 [7][8][24]。在神经系统中，IL-6/sIL-6R与IL-1β或TNF-α协同上调IL-6形成正反馈 [8]。此外，IL-1β可诱导GRP78上调并经p38 MAPK促进IL-6释放 [21,22]，揭示了炎症信号与细胞应激间的交叉调控。
3. 病理生理学意义与疾病关联
IL-6、IL-1β与TNF-α异常表达与多种疾病密切相关：
- 在代谢性疾病中，三者在糖尿病视网膜病变中协同升高，促进血管生成与神经损伤 [3]；
- 在SLE中，其血清水平与疾病活动度呈正相关 [4]；
- 在肿瘤中，IL-6/STAT3信号持续激活驱动细胞增殖与免疫逃逸 [10][11]；
- 在感染性疾病与脓毒症中，NLRP3炎性体驱动的IL-1β/IL-18释放加剧组织损伤 [12]。
这表明三者构成炎症“核心三角”，其动态平衡对维持免疫稳态至关重要。
4. 治疗策略与临床前景
针对IL-6、IL-1β与TNF-α的靶向治疗已在多种疾病中取得突破：
- IL-6阻断剂（如托珠单抗）在类风湿关节炎及细胞因子风暴中效果显著；
- IL-1β抑制剂（Canakinumab）可降低心血管炎症；
- TNF-α拮抗剂（Infliximab、Etanercept）已成为炎症性疾病的标准疗法。
此外，miRNA调控、炎性体抑制剂及天然化合物多靶点干预为新一代抗炎策略提供方向。
5. 总结
IL-6、IL-1β与TNF-α是炎症信号网络的核心枢纽，在维系免疫平衡与介导病理炎症中发挥关键作用。三者通过NF-κB、MAPK及JAK/STAT3等通路形成多层交叉调控网络，其精确的时空表达决定了炎症反应的强度与持续性。异常激活或反馈失衡可导致慢性炎症、组织损伤及多种疾病的发生，包括代谢紊乱、自身免疫病、神经炎症与肿瘤等。系统解析三者的信号通路与相互作用，不仅深化了对炎症反应分子机制的理解，也为精准抗炎与多靶点治疗提供理论基础。
值得注意的是，IL-6、IL-1β与TNF-α的检测在科研与临床研究中同样具有重要意义。通过定量监测这些关键炎症介质的水平，可用于评估疾病活动度、验证炎症模型、监控治疗反应以及筛选潜在生物标志物。准确、灵敏的检测手段能够为基础研究提供可靠数据支撑，并为临床决策提供早期预警依据。
华美生物提供的炎症因子ELISA检测试剂盒套装现涵盖IL-6、IL-1β、TNF-α等多种核心炎症因子，能够帮助科研人员高效评估炎症反应的分子特征，加速机制研究与转化应用进程。
参考文献：
[1] Paolo Tieri, Silvana Valensin, Vito Latora, Gastone C. Castellani, Massimo Marchiori, Daniel Remondini, Claudio Franceschi.(2004). Quantifying the relevance of different mediators in the human immune cell network.
[2] Sheng-Rong Zou, Yu-Jing Peng, Zhong-Wei Guo, Ta Zhou, Chang-gui Gu, Da-Ren He.(2007). An Empirical Study of Immune System Based On Bipartite Network.
[3] Songfu Feng, Honghua Yu, Ying Yu, Yu Geng, Dongli Li, Chun Yang, Qingjun Lv, Li Lu, Ting Liu, Guodong Li, Ling Yuan.(2018). Levels of Inflammatory Cytokines IL-1β, IL-6, IL-8, IL-17A, and TNF-α in Aqueous Humour of Patients with Diabetic Retinopathy.
[4] V. Umare, V. Pradhan, M. Nadkar, A. Rajadhyaksha, M. Patwardhan, K. Ghosh, A. Nadkarni.(2014). Effect of Proinflammatory Cytokines (IL-6, TNF-α, and IL-1β) on Clinical Manifestations in Indian SLE Patients.
[5] Sheng-Rong Zou, Zhong-Wei Guo, Yu-Jing Peng, Ta Zhou, Chang-Gui Gu, Da-Ren He.(2007). A Brand-new Research Method of Neuroendocrine System.
[6] D. Florescu, M. Boldeanu, Robert-Emmanuel Șerban, L. Florescu, M. Șerbănescu, Mihaela Ionescu, L. Streba, Cristian Constantin, C. Vere.(2023). Correlation of the Pro-Inflammatory Cytokines IL-1β, IL-6, and TNF-α, Inflammatory Markers, and Tumor Markers with the Diagnosis and Prognosis of Colorectal Cancer.
[7] D. Skelly, E. Hennessy, M. Dansereau, C. Cunningham.(2013). A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1Β, TNF-α and IL-6 Challenges in C57BL/6 Mice.
[8] B. Barton, T. Murphy, Patricia V Adem, R. Watson, R. Irwin, Hosea F. S. Huang.(2001). IL-6 signaling by STAT3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells.
[9] S. Kwok, M. Cho, Yang-Mi Her, Hye‐Joa Oh, Mi-Kyung Park, Seon-Yeong Lee, Yun‐Ju Woo, J. Ju, Kyung-Su Park, Ho‐Youn Kim, Sung-Hwan Park.(2012). TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in patients with primary Sjogren’s syndrome.
[10] W. Feng, Hongrui Liu, Tingting Luo, Di Liu, Juan Du, Jing Sun, Wei Wang, Xiuchun Han, Kaiyun Yang, Jie Guo, N. Amizuka, Minqi Li.(2017). Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways.
[11] Nicholas J. Van Wagoner, Jae-Wook Oh, P. Repovic, E. Benveniste.(1999). Interleukin-6 (IL-6) Production by Astrocytes: Autocrine Regulation by IL-6 and the Soluble IL-6 Receptor.
[12] E. Helset, T. Sildnes, R. Seljelid, Z. Konopski.(1993). Endothelin-1 stimulates human monocytes in vitro to release TNF-α , IL-1β and IL-6.
[13] Juan Wu, Ping Niu, Yueqiang Zhao, Yan-li Cheng, Weiping Chen, Lan Lin, J. Lu, Xuefeng Cheng, Zhiliang Xu.(2019). Impact of miR-223-3p and miR-2909 on inflammatory factors IL-6, IL-1ß, and TNF-α, and the TLR4/TLR2/NF-κB/STAT3 signaling pathway induced by lipopolysaccharide in human adipose stem cells.
[14] Xin Shao, Jialong Li, Huidan Zhang, Xuhui Zhang, Chongzheng Sun, Ouyang Xin, Yong Wang, Xiyang Wu, Chunbo Chen.(2023). Anti-inflammatory effects and molecular mechanisms of bioactive small molecule garlic polysaccharide.
[15] Xinli Liu, Xu-tao Zhang, Jin Meng, Hong-Fei Zhang, Yong Zhao, Chen Li, Yang Sun, Q. Mei, Feng Zhang, Tao Zhang.(2017). ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.
[16] J. Osborne, P. Moore, Yuan Chang.(1999). KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways.
[17] Hanchao Gao, Qing Zhang, Jicheng Chen, D. Cooper, H. Hara, Pengfei Chen, Ling Wei, Yanli Zhao, Jia Xu, Zesong Li, Z. Cai, Shaodong Luan, Lisha Mou.(2018). Porcine IL‐6, IL‐1β, and TNF‐α regulate the expression of pro‐inflammatory‐related genes and tissue factor in human umbilical vein endothelial cells.
[18] Sara J Hamis, Fiona R Macfarlane.(2020). A single-cell mathematical model of SARS-CoV-2 induced pyroptosis and the effects of anti-inflammatory intervention.
[19] K. Fujimura, T. Karasawa, T. Komada, N. Yamada, C. Baatarjav, T. Matsumura, H. Mizukami, K. Kario, M. Takahashi.(2023). NLRP3 inflammasome-produced pro-inflammatory cytokines IL-1b and IL-18 are critical exacerbating factors of septic cardiomyopathy.
[20] Shanmuga S. Mahalingam, S. Jayaraman, Adhvika Arunkumar, Holly M. Dudley, Dona Anthony, C. Shive, Jeffrey M. Jacobson, P. Pandiyan.(2023). Distinct SARS-CoV-2 specific NLRP3 and IL-1β responses in T cells of aging patients during acute COVID-19 infection.
[21] Kunjan Khanna, Hui Yan, Muneshwar Mehra, N. Rohatgi, G. Mbalaviele, E. Mellins, R. Faccio.(2023). Tmem178 Negatively Regulates IL‐1β Production Through Inhibition of the NLRP3 Inflammasome.
[22] Gang Gao, F. Chang, Ting Zhang, Xinhu Huang, Chen Yu, Zhixia Hu, Mingming Ji, Yufen Duan.(2019). Naringin Protects Against Interleukin 1β (IL-1β)-Induced Human Nucleus Pulposus Cells Degeneration via Downregulation Nuclear Factor kappa B (NF-κB) Pathway and p53 Expression.
[23] C. Yu, W. Miao, Y. Y. Zhang, M. Zou, X. F. Yan.(2018). Inhibition of miR-126 protects chondrocytes from IL-1β induced inflammation via upregulation of Bcl-2.
[24] O. Krupkova, A. Sadowska, T. Kameda, W. Hitzl, O. Hausmann, Juergen Klasen, K. Wuertz-Kozak.(2018). p38 MAPK Facilitates Crosstalk Between Endoplasmic Reticulum Stress and IL-6 Release in the Intervertebral Disc.
[25] Yongqiang Liu, Qian Li, Zhi-Rui Gao, Fangcao Lei, Xuefeng Gao.(2021). Circ-SPG11 knockdown hampers IL-1β-induced osteoarthritis progression via targeting miR-337-3p/ADAMTS5.
[26] H. Zhang, Cheng Chen, Jie Song.(2022). microRNA-4701-5p protects against interleukin-1β induced human chondrocyte CHON-001 cells injury via modulating HMGA1.
[27] Yunzhou Zuo, Changjun Xiong, X. Gan, Wei Xie, Xiaokang Yan, Yanzhao Chen, Xu-gui Li.(2023). LncRNA HAGLR silencing inhibits IL-1β-induced chondrocytes inflammatory injury via miR-130a-3p/JAK1 axis.
[28] Fang Li, Hua Huang, Ping Zhao, Jie Jiang, Xufeng Ding, Donxgue Lu, Lijiang Ji.(2023). Curculigoside mitigates dextran sulfate sodium-induced colitis by activation of KEAP1-NRF2 interaction to inhibit oxidative damage and autophagy of intestinal epithelium barrier.
[29] Zhen-Tao Mo, Jie Zheng, Yu Liao.(2021). Icariin inhibits the expression of IL-1β, IL-6 and TNF-α induced by OGD/R through the IRE1/XBP1s pathway in microglia.
[30] Yang Zhang, Li-fei Wang, Liping Bai, R. Jiang, Jian-bo Wu, Yuan Li.(2022). Ebosin Attenuates the Inflammatory Responses Induced by TNF-α through Inhibiting NF-κB and MAPK Pathways in Rat Fibroblast-Like Synoviocytes.
[31] P. Pothacharoen, R. Chaiwongsa, Theerawut Chanmee, Orapin Insuan, Thanchanok Wongwichai, Phornpimon Janchai, P. Vaithanomsat.(2021). Bromelain Extract Exerts Antiarthritic Effects via Chondroprotection and the Suppression of TNF-α–Induced NF-κB and MAPK Signaling.
[32] Alexandra M S Carvalho, Luana Heimfarth, E. W. Pereira, Fabrício S Oliveira, I. A. Menezes, H. Coutinho, Laurent Picot, Â. Antoniolli, J. Quintans, L. Quintans-Júnior.(2020). Phytol, a Chlorophyll Component, Produces Antihyperalgesic, Anti-inflammatory, and Antiarthritic Effects: Possible NFκB Pathway Involvement and Reduced Levels of the Proinflammatory Cytokines TNF-α and IL-6.
[33] Fan Zhang, Joseph R. Mears, L. Shakib, Jessica I. Beynor, Sara Shanaj, I. Korsunsky, A. Nathan, L. Donlin, S. Raychaudhuri.(2021). IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation.
[34] Abdush Salam Pramanik, Bibaswan Dey, G. P. Raja Sekhar.(2023). A Two-Phase Model of Early Atherosclerotic Plaque Development with LDL Toxicity Effects.