III型干扰素在炎症性肠病肠道屏障调控中的 作用研究进展
Research Progress on the Role of Type III Interferons in the Regulation of Intestinal Barrier in Inflammatory Bowel Disease
DOI: 10.12677/acm.2026.1641724, PDF,   
作者: 王 坤, 杨 桦*：重庆医科大学，重庆；重庆市人民医院普外科，重庆
关键词: 炎症性肠病；肠道屏障；III型干扰素；IL-28A；STAT1；黏膜愈合；Inflammatory Bowel Disease； Intestinal Barrier； Type III Interferon； IL-28A； STAT1； Mucosal Healing
摘要: 炎症性肠病(IBD)是一种全球发病率持续上升的慢性胃肠道炎症性疾病，其核心发病机制涉及遗传易感个体的肠道免疫稳态失衡，表现为免疫反应失调、细胞因子异常、肠道菌群紊乱及肠道屏障功能损伤。肠道屏障的完整性是防止微生物易位和炎症级联反应的关键。尽管针对促炎细胞因子和淋巴细胞迁移的生物制剂及小分子药物已应用于临床，但患者反应的异质性仍是挑战。近年来，III型干扰素因其受体IL-28R主要表达于肠道上皮等屏障部位而受到关注，提示其可能在局部黏膜免疫中发挥特异性作用。目前关于IL-28A在IBD发病机制及肠道修复中的作用尚存争议。本文综述了IBD的病理生理基础、现有治疗策略的局限性，并重点探讨了IL-28/STAT1信号通路在调节肠道上皮屏障功能与黏膜稳态中的双重作用及潜在机制。深入理解IL-28A在肠道微环境中的复杂角色，或可为IBD的治疗提供新的干预靶点和理论依据。
Abstract: Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder with a continuously increasing global incidence. Its core pathogenesis involves the imbalance of intestinal immune homeostasis in genetically susceptible individuals, characterized by dysregulated immune responses, abnormal cytokines, disturbed gut microbiota, and impaired intestinal barrier function. The integrity of the intestinal barrier is crucial for preventing microbial translocation and inflammatory cascades. Although biological agents and small-molecule drugs targeting pro-inflammatory cytokines and lymphocyte migration have been applied clinically, the heterogeneity of patient responses remains a major challenge. In recent years, type III interferons have attracted considerable attention because their receptor IL-28R is predominantly expressed in barrier sites such as the intestinal epithelium, suggesting that they may exert specific effects in local mucosal immunity. Currently, the role of IL-28A in the pathogenesis of IBD and intestinal repair remains controversial. This review summarizes the pathophysiological basis of IBD and the limitations of current therapeutic strategies, with a focus on the dual role and underlying mechanisms of the IL-28/STAT1 signaling pathway in regulating intestinal epithelial barrier function and mucosal homeostasis. A deeper understanding of the complex role of IL-28A in the intestinal microenvironment may provide novel intervention targets and theoretical evidence for the treatment of IBD.
文章引用：王坤, 杨桦. III型干扰素在炎症性肠病肠道屏障调控中的 作用研究进展[J]. 临床医学进展, 2026, 16(4): 4532-4538. https://doi.org/10.12677/acm.2026.1641724

参考文献

[1] Strober, W., Fuss, I. and Mannon, P. (2007) The Fundamental Basis of Inflammatory Bowel Disease. Journal of Clinical Investigation, 117, 514-521. [Google Scholar] [CrossRef] [PubMed]
[2] Kaser, A., Zeissig, S. and Blumberg, R.S. (2010) Inflammatory Bowel Disease. Annual Review of Immunology, 28, 573-621. [Google Scholar] [CrossRef] [PubMed]
[3] Torres, J., Mehandru, S., Colombel, J. and Peyrin-Biroulet, L. (2017) Crohn’s Disease. The Lancet, 389, 1741-1755. [Google Scholar] [CrossRef] [PubMed]
[4] Di Narzo, A.F., Peters, L.A., Argmann, C., Stojmirovic, A., Perrigoue, J., Li, K., et al. (2016) Blood and Intestine eQTLs from an Anti-TNF-Resistant Crohn’s Disease Cohort Inform IBD Genetic Association Loci. Clinical and Translational Gastroenterology, 7, e177. [Google Scholar] [CrossRef] [PubMed]
[5] Lloyd-Price, J., Arze, C., Ananthakrishnan, A.N., Schirmer, M., Avila-Pacheco, J., Poon, T.W., et al. (2019) Multi-Omics of the Gut Microbial Ecosystem in Inflammatory Bowel Diseases. Nature, 569, 655-662. [Google Scholar] [CrossRef] [PubMed]
[6] Halfvarson, J., Brislawn, C.J., Lamendella, R., Vázquez-Baeza, Y., Walters, W.A., Bramer, L.M., et al. (2017) Dynamics of the Human Gut Microbiome in Inflammatory Bowel Disease. Nature Microbiology, 2, Article No. 17004. [Google Scholar] [CrossRef] [PubMed]
[7] Vieira-Silva, S., Sabino, J., Valles-Colomer, M., Falony, G., Kathagen, G., Caenepeel, C., et al. (2019) Quantitative Microbiome Profiling Disentangles Inflammation-and Bile Duct Obstruction-Associated Microbiota Alterations across PSC/IBD Diagnoses. Nature Microbiology, 4, 1826-1831. [Google Scholar] [CrossRef] [PubMed]
[8] Luissint, A., Parkos, C.A. and Nusrat, A. (2016) Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology, 151, 616-632. [Google Scholar] [CrossRef] [PubMed]
[9] Oami, T., Shimazui, T., Yumoto, T., Otani, S., Hayashi, Y. and Coopersmith, C.M. (2025) Gut Integrity in Intensive Care: Alterations in Host Permeability and the Microbiome as Potential Therapeutic Targets. Journal of Intensive Care, 13, Article No. 16. [Google Scholar] [CrossRef] [PubMed]
[10] Lee, S.H. (2015) Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases. Intestinal Research, 13, 11-18. [Google Scholar] [CrossRef] [PubMed]
[11] Neurath, M.F. (2014) Cytokines in Inflammatory Bowel Disease. Nature Reviews Immunology, 14, 329-342. [Google Scholar] [CrossRef] [PubMed]
[12] Nalleweg, N., Chiriac, M.T., Podstawa, E., Lehmann, C., Rau, T.T., Atreya, R., et al. (2015) IL-9 and Its Receptor Are Predominantly Involved in the Pathogenesis of Uc. Gut, 64, 743-755. [Google Scholar] [CrossRef] [PubMed]
[13] Heller, F., Florian, P., Bojarski, C., Richter, J., Christ, M., Hillenbrand, B., et al. (2005) Interleukin-13 Is the Key Effector Th2 Cytokine in Ulcerative Colitis That Affects Epithelial Tight Junctions, Apoptosis, and Cell Restitution. Gastroenterology, 129, 550-564. [Google Scholar] [CrossRef] [PubMed]
[14] Günther, C., Neumann, H., Neurath, M.F. and Becker, C. (2013) Apoptosis, Necrosis and Necroptosis: Cell Death Regulation in the Intestinal Epithelium. Gut, 62, 1062-1071. [Google Scholar] [CrossRef] [PubMed]
[15] Fantini, M.C., Becker, C., Tubbe, I., et al. (2006) Transforming Growth Factor Beta Induced FoxP3+ Regulatory T Cells Suppress Th1 Mediated Experimental Colitis. Gut, 55, 671-680. [Google Scholar] [CrossRef] [PubMed]
[16] Neurath, M.F. (2014) New Targets for Mucosal Healing and Therapy in Inflammatory Bowel Diseases. Mucosal Immunology, 7, 6-19. [Google Scholar] [CrossRef] [PubMed]
[17] Chang, J.T. (2020) Pathophysiology of Inflammatory Bowel Diseases. New England Journal of Medicine, 383, 2652-2664. [Google Scholar] [CrossRef] [PubMed]
[18] Kotenko, S.V., Gallagher, G., Baurin, V.V., Lewis-Antes, A., Shen, M., Shah, N.K., et al. (2003) IFN-λs Mediate Antiviral Protection through a Distinct Class II Cytokine Receptor Complex. Nature Immunology, 4, 69-77. [Google Scholar] [CrossRef] [PubMed]
[19] Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T.E., et al. (2003) IL-28, IL-29 and Their Class II Cytokine Receptor IL-28R. Nature Immunology, 4, 63-68. [Google Scholar] [CrossRef] [PubMed]
[20] Lazear, H.M., Nice, T.J. and Diamond, M.S. (2015) Interferon-λ: Immune Functions at Barrier Surfaces and beyond. Immunity, 43, 15-28. [Google Scholar] [CrossRef] [PubMed]
[21] Li, Y., Cheng, H., Zuo, X., Sheng, Y., Zhou, F., Tang, X., et al. (2013) Association Analyses Identifying Two Common Susceptibility Loci Shared by Psoriasis and Systemic Lupus Erythematosus in the Chinese Han Population. Journal of Medical Genetics, 50, 812-818. [Google Scholar] [CrossRef] [PubMed]
[22] Siebler, J., Wirtz, S., Weigmann, B., Atreya, I., Schmitt, E., Kreft, A., et al. (2007) IL-28A Is a Key Regulator of T-Cell-Mediated Liver Injury via the T-Box Transcription Factor T-Bet. Gastroenterology, 132, 358-371. [Google Scholar] [CrossRef] [PubMed]
[23] Koch, S. and Finotto, S. (2015) Role of Interferon-λ in Allergic Asthma. Journal of Innate Immunity, 7, 224-230. [Google Scholar] [CrossRef] [PubMed]
[24] Blazek, K., Eames, H.L., Weiss, M., Byrne, A.J., Perocheau, D., Pease, J.E., et al. (2015) IFN-λ Resolves Inflammation via Suppression of Neutrophil Infiltration and IL-1β Production. Journal of Experimental Medicine, 212, 845-853. [Google Scholar] [CrossRef] [PubMed]
[25] Lazear, H.M., Daniels, B.P., Pinto, A.K., Huang, A.C., Vick, S.C., Doyle, S.E., et al. (2015) Interferon-λ Restricts West Nile Virus Neuroinvasion by Tightening the Blood-Brain Barrier. Science Translational Medicine, 7, 284ra59. [Google Scholar] [CrossRef] [PubMed]
[26] Doyle, S.E., Schreckhise, H., Khuu-Duong, K., Henderson, K., Rosler, R., Storey, H., et al. (2006) Interleukin-29 Uses a Type 1 Interferon-Like Program to Promote Antiviral Responses in Human Hepatocytes. Hepatology, 44, 896-906. [Google Scholar] [CrossRef] [PubMed]
[27] Odendall, C., Dixit, E., Stavru, F., Bierne, H., Franz, K.M., Durbin, A.F., et al. (2014) Diverse Intracellular Pathogens Activate Type III Interferon Expression from Peroxisomes. Nature Immunology, 15, 717-726. [Google Scholar] [CrossRef] [PubMed]
[28] Baños-Lara, M.D.R., Harvey, L., Mendoza, A., Simms, D., Chouljenko, V.N., Wakamatsu, N., et al. (2015) Impact and Regulation of Lambda Interferon Response in Human Metapneumovirus Infection. Journal of Virology, 89, 730-742. [Google Scholar] [CrossRef] [PubMed]
[29] McElrath, C., Espinosa, V., Lin, J., Peng, J., Sridhar, R., Dutta, O., et al. (2021) Critical Role of Interferons in Gastrointestinal Injury Repair. Nature Communications, 12, Article No. 2624. [Google Scholar] [CrossRef] [PubMed]
[30] Pott, J., Mahlakõiv, T., Mordstein, M., Duerr, C.U., Michiels, T., Stockinger, S., et al. (2011) IFN-λ Determines the Intestinal Epithelial Antiviral Host Defense. Proceedings of the National Academy of Sciences, 108, 7944-7949. [Google Scholar] [CrossRef] [PubMed]
[31] Chiriac, M.T., Buchen, B., Wandersee, A., Hundorfean, G., Günther, C., Bourjau, Y., et al. (2017) Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice with Colitis and Is Increased in Mucosa of Patients with Inflammatory Bowel Disease. Gastroenterology, 153, 123-138. [Google Scholar] [CrossRef] [PubMed]
[32] Yu, M., Wang, Q., Ma, Y., Li, L., Yu, K., Zhang, Z., et al. (2018) Aryl Hydrocarbon Receptor Activation Modulates Intestinal Epithelial Barrier Function by Maintaining Tight Junction Integrity. International Journal of Biological Sciences, 14, 69-77. [Google Scholar] [CrossRef] [PubMed]
[33] Li, X., Li, Q., Xiong, B., Chen, H., Wang, X. and Zhang, D. (2022) Discoidin Domain Receptor 1 (DDR1) Promote Intestinal Barrier Disruption in Ulcerative Colitis through Tight Junction Proteins Degradation and Epithelium Apoptosis. Pharmacological Research, 183, Article 106368. [Google Scholar] [CrossRef] [PubMed]
[34] Samak, G., Chaudhry, K.K., Gangwar, R., Narayanan, D., Jaggar, J.H. and Rao, R. (2015) Calcium/Ask1/MKK7/JNK2/c-Src Signalling Cascade Mediates Disruption of Intestinal Epithelial Tight Junctions by Dextran Sulfate Sodium. Biochemical Journal, 465, 503-515. [Google Scholar] [CrossRef] [PubMed]
[35] Koltsida, O., Hausding, M., Stavropoulos, A., Koch, S., Tzelepis, G., Übel, C., et al. (2011) IL-28A (IFN-λ2) Modulates Lung DC Function to Promote Th1 Immune Skewing and Suppress Allergic Airway Disease. EMBO Molecular Medicine, 3, 348-361. [Google Scholar] [CrossRef] [PubMed]
[36] Xu, P., Becker, H., Elizalde, M., Pierik, M., Masclee, A. and Jonkers, D. (2021) Interleukin-28A Induces Epithelial Barrier Dysfunction in CD Patient-Derived Intestinal Organoids. American Journal of Physiology-Gastrointestinal and Liver Physiology, 320, G689-G699. [Google Scholar] [CrossRef] [PubMed]
[37] Li, L., Zhou, C., Li, T., Xiao, W., Yu, M. and Yang, H. (2021) Interleukin-28A Maintains the Intestinal Epithelial Barrier Function through Regulation of Claudin-1. Annals of Translational Medicine, 9, Article 365. [Google Scholar] [CrossRef] [PubMed]

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