炎癥“核心三角”的深度對話：IL-6、IL-1β與TNF-α如何共舞，推動疾病進展？
日期：2025-11-05 17:31:33
炎癥是機體維持穩(wěn)態(tài)與應(yīng)對損傷的關(guān)鍵防御機制，但其調(diào)控失衡則成為多種慢性疾病的重要病理基礎(chǔ)。白細胞介素-6（IL-6）、白細胞介素-1β（IL-1β）和腫瘤壞死因子-α（TNF-α）被廣泛認為是炎癥反應(yīng)的核心促炎細胞因子，構(gòu)成免疫網(wǎng)絡(luò)的關(guān)鍵樞紐。
深入理解IL-6、IL-1β與TNF-α的分子網(wǎng)絡(luò)，對于精準診斷及開發(fā)多靶點炎癥治療策略具有重要意義。本文旨在闡明三種細胞因子在炎癥反應(yīng)中的分子機制及其病理生理意義，探討三者在不同疾病中的協(xié)同作用與動態(tài)平衡，以期為您的研究提供幫助。
1. 什么是核心促炎細胞因子？
炎癥是機體抵御感染、修復(fù)組織及維持穩(wěn)態(tài)的重要生理過程。該反應(yīng)通過復(fù)雜的細胞與分子事件清除有害刺激并促進組織修復(fù)。然而，若炎癥反應(yīng)持續(xù)或調(diào)控失衡，便會轉(zhuǎn)化為慢性炎癥，誘發(fā)代謝紊亂、自身免疫病、神經(jīng)退行性疾病及腫瘤等多種病理狀態(tài)。研究表明，細胞因子網(wǎng)絡(luò)在炎癥反應(yīng)中起核心調(diào)控作用，其中IL-6、IL-1β和TNF-α是關(guān)鍵的促炎信號介質(zhì) [1]。
這些細胞因子由巨噬細胞、T細胞、B細胞及成纖維細胞等多種免疫細胞分泌，通過與特異受體結(jié)合激活下游信號通路，從而調(diào)節(jié)免疫反應(yīng)與細胞存活。免疫網(wǎng)絡(luò)分析顯示，IL-6、IL-1β和TNF-α在拓撲結(jié)構(gòu)中具有最高中心性，是維持免疫系統(tǒng)穩(wěn)態(tài)的重要節(jié)點 [2]。它們的異常激活與糖尿病視網(wǎng)膜病變（DR）、系統(tǒng)性紅斑狼瘡（SLE）和結(jié)直腸癌（CRC）等疾病密切相關(guān) [3-6]。
2. IL-6、IL-1β與TNF-α的信號通路與調(diào)控
IL-6、IL-1β與TNF-α是炎癥反應(yīng)的三大核心介質(zhì)。它們通過特異受體啟動信號級聯(lián)，激活轉(zhuǎn)錄因子，調(diào)控多種促炎基因表達，從而驅(qū)動炎癥過程。本章將系統(tǒng)分析三者的信號轉(zhuǎn)導(dǎo)機制、相互調(diào)控與分子網(wǎng)絡(luò)。
2.1 IL-6信號傳導(dǎo)與效應(yīng)
IL-6信號主要通過JAK/STAT3通路實現(xiàn)。IL-6與膜結(jié)合或可溶性IL-6受體（IL-6R）結(jié)合后，與gp130形成復(fù)合體，誘導(dǎo)gp130二聚化并激活JAK家族激酶。隨后STAT3被磷酸化、二聚化并轉(zhuǎn)位入核，調(diào)控急性期蛋白及炎癥相關(guān)基因表達 [8]。
IL-6的反式信號（trans-signaling）在炎癥調(diào)控中尤為關(guān)鍵。例如，IL-6/sIL-6R復(fù)合體能激活缺乏膜型IL-6R的細胞，增強破骨細胞分化與炎癥反應(yīng) [9,10]。在中樞神經(jīng)系統(tǒng)中，IL-6/sIL-6R可與TNF-α或IL-1β協(xié)同，誘導(dǎo)星形膠質(zhì)細胞IL-6自分泌表達 [11]。此外，miR-223-3p通過負向調(diào)控STAT3形成反饋回路，而TNF-α可上調(diào)該miRNA以平衡炎癥 [12,13]。
在腫瘤中，IL-6/STAT3軸異常激活促進癌細胞增殖與轉(zhuǎn)移，如前列腺癌及肺癌中均觀察到STAT3持續(xù)磷酸化 [8,15]。病毒因子如KSHV編碼的vIL-6亦可激活宿主STAT3通路，提示該信號軸在感染性腫瘤中的重要作用 [16]。
2.2 IL-1β信號傳導(dǎo)與效應(yīng)
IL-1β以無活性的pro-IL-1β形式存在，其成熟依賴NLRP3炎性體介導(dǎo)的Caspase-1激活。炎性體由NLRP3、ASC和Caspase-1組成，能感知LPS、ATP及病毒等刺激，促使IL-1β與IL-18成熟釋放 [17-20]。
成熟的IL-1β與IL-1R結(jié)合后，啟動MyD88依賴性通路，激活I(lǐng)RAKs與TRAF6，進而觸發(fā)NF-κB與MAPK通路，誘導(dǎo)TNF-α、IL-6等促炎基因轉(zhuǎn)錄 [21-24]。
在骨關(guān)節(jié)炎、腸炎及膿毒癥心肌病等疾病中，IL-1β驅(qū)動軟骨細胞凋亡、基質(zhì)降解與心肌功能障礙 [19][25][27]。其調(diào)控網(wǎng)絡(luò)涉及多種非編碼RNA：如miR-4701-5p通過抑制HMGA1緩解炎癥，lncRNA HAGLR沉默則通過miR-130a-3p/JAK1軸減輕軟骨細胞損傷 [26][27]。
天然產(chǎn)物（如大蒜多糖）可通過抑制NF-κB/STAT3活化顯著降低IL-1β、IL-6與TNF-α水平 [14]。這些研究揭示IL-1β在炎癥級聯(lián)反應(yīng)中的核心驅(qū)動力與多層調(diào)控機制。
2.3 TNF-α信號傳導(dǎo)與效應(yīng)
TNF-α通過TNFR1和TNFR2受體介導(dǎo)信號轉(zhuǎn)導(dǎo)，廣泛調(diào)控細胞存活、凋亡及炎癥反應(yīng)。其主要通路包括NF-κB和MAPK激活級聯(lián) [29-32]。TNFR1活化后募集TRADD、RIP1與TRAF2，形成信號復(fù)合物并激活I(lǐng)KK復(fù)合體。IKKβ磷酸化IκBα后促使其降解，NF-κB二聚體（p65/p50）轉(zhuǎn)位入核并誘導(dǎo)IL-6、IL-1β、CCL2等基因表達 [30][22]。同時，TNF-α還通過p38和JNK調(diào)節(jié)炎癥、凋亡與應(yīng)激反應(yīng) [24][30]。
在類風(fēng)濕關(guān)節(jié)炎（RA）中，TNF-α激活滑膜細胞NF-κB/MAPK信號，促進MMPs與IL-6釋放，驅(qū)動關(guān)節(jié)破壞 [30]；在動脈粥樣硬化中，TNF-α與MCP-1共同參與早期斑塊形成 [34]。此外，其與IFN-γ可協(xié)同誘導(dǎo)CXCL10?炎性巨噬細胞表型，揭示不同炎癥疾病間共享的病理機制 [33]。在椎間盤退變與異種移植模型中，TNF-α的持續(xù)激活同樣導(dǎo)致組織損傷與排斥反應(yīng) [17][22]。綜上，TNF-α通過NF-κB與MAPK雙通路構(gòu)成炎癥反應(yīng)的核心調(diào)控軸。
2.4 細胞因子信號通路整合分析
IL-6、IL-1β與TNF-α下游信號具有顯著交叉性。IL-1β和TNF-α通過NF-κB/MAPK驅(qū)動炎癥擴散，而IL-6以JAK/STAT3為主軸維持反應(yīng)持續(xù)。天然化合物Ebosin及植物醇通過抑制IKKβ、p38與JNK磷酸化有效降低炎癥反應(yīng) [20][28]。這種信號交叉使炎癥反應(yīng)具備可塑性，也為多靶點干預(yù)提供理論依據(jù)。
2.5 細胞因子間的交叉與網(wǎng)絡(luò)調(diào)控
IL-6、IL-1β與TNF-α間的相互誘導(dǎo)與反饋調(diào)節(jié)構(gòu)建了復(fù)雜炎癥網(wǎng)絡(luò)。
研究表明，IL-1β與TNF-α相互誘導(dǎo)并協(xié)同促進IL-6表達，形成炎癥放大回路 [7][8][24]。在神經(jīng)系統(tǒng)中，IL-6/sIL-6R與IL-1β或TNF-α協(xié)同上調(diào)IL-6形成正反饋 [8]。此外，IL-1β可誘導(dǎo)GRP78上調(diào)并經(jīng)p38 MAPK促進IL-6釋放 [21,22]，揭示了炎癥信號與細胞應(yīng)激間的交叉調(diào)控。
3. 病理生理學(xué)意義與疾病關(guān)聯(lián)
IL-6、IL-1β與TNF-α異常表達與多種疾病密切相關(guān)：
- 在代謝性疾病中，三者在糖尿病視網(wǎng)膜病變中協(xié)同升高，促進血管生成與神經(jīng)損傷 [3]；
- 在SLE中，其血清水平與疾病活動度呈正相關(guān) [4]；
- 在腫瘤中，IL-6/STAT3信號持續(xù)激活驅(qū)動細胞增殖與免疫逃逸 [10][11]；
- 在感染性疾病與膿毒癥中，NLRP3炎性體驅(qū)動的IL-1β/IL-18釋放加劇組織損傷 [12]。
這表明三者構(gòu)成炎癥“核心三角”，其動態(tài)平衡對維持免疫穩(wěn)態(tài)至關(guān)重要。
4. 治療策略與臨床前景
針對IL-6、IL-1β與TNF-α的靶向治療已在多種疾病中取得突破：
- IL-6阻斷劑（如托珠單抗）在類風(fēng)濕關(guān)節(jié)炎及細胞因子風(fēng)暴中效果顯著；
- IL-1β抑制劑（Canakinumab）可降低心血管炎癥；
- TNF-α拮抗劑（Infliximab、Etanercept）已成為炎癥性疾病的標準療法。
此外，miRNA調(diào)控、炎性體抑制劑及天然化合物多靶點干預(yù)為新一代抗炎策略提供方向。
5. 總結(jié)
IL-6、IL-1β與TNF-α是炎癥信號網(wǎng)絡(luò)的核心樞紐，在維系免疫平衡與介導(dǎo)病理炎癥中發(fā)揮關(guān)鍵作用。三者通過NF-κB、MAPK及JAK/STAT3等通路形成多層交叉調(diào)控網(wǎng)絡(luò)，其精確的時空表達決定了炎癥反應(yīng)的強度與持續(xù)性。異常激活或反饋失衡可導(dǎo)致慢性炎癥、組織損傷及多種疾病的發(fā)生，包括代謝紊亂、自身免疫病、神經(jīng)炎癥與腫瘤等。系統(tǒng)解析三者的信號通路與相互作用，不僅深化了對炎癥反應(yīng)分子機制的理解，也為精準抗炎與多靶點治療提供理論基礎(chǔ)。
值得注意的是，IL-6、IL-1β與TNF-α的檢測在科研與臨床研究中同樣具有重要意義。通過定量監(jiān)測這些關(guān)鍵炎癥介質(zhì)的水平，可用于評估疾病活動度、驗證炎癥模型、監(jiān)控治療反應(yīng)以及篩選潛在生物標志物。準確、靈敏的檢測手段能夠為基礎(chǔ)研究提供可靠數(shù)據(jù)支撐，并為臨床決策提供早期預(yù)警依據(jù)。
華美生物提供的炎癥因子ELISA檢測試劑盒套裝現(xiàn)涵蓋IL-6、IL-1β、TNF-α等多種核心炎癥因子，能夠幫助科研人員高效評估炎癥反應(yīng)的分子特征，加速機制研究與轉(zhuǎn)化應(yīng)用進程。
參考文獻：
[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 ?erban, L. Florescu, M. ?erb?nescu, 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-1?, 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, ?. 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.
