IL‐17 家族在炎症性肠病发病及治疗中的研究进展

Research progress of the IL‐17 family in the pathogenesis and treatment of inflammatory bowel disease

摘要

炎症性肠病（IBD)是一种累及回肠、结肠和直肠的特发性肠道炎性疾病，IBD 的发病机制涉及多种因素，主要是环境因素、遗传因素、肠道微生态和免疫失衡。白细胞介素⁃17（IL⁃17）家族是辅助性 T 细胞 17（Th17）细胞免疫应答的核心效应细胞因子，在宿主防御和炎症病理中发挥至关重要的作用，参与多种免疫介导的炎症性疾病，近年来的研究发现 IL⁃17 家族在 IBD 中发挥更为复杂的重要作用。本文就 IL⁃17 家族对 IBD 发生发展及作为治疗靶点的研究进展进行综述，为临床决策提供依据。

Abstract

Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel condition that affects the ileum, colon, and rectum. The pathogenesis of IBD involves multiple factors, primarily environmental influences, genetic predisposition, gut microbiota dysbiosis, and immune dysregulation. The interleukin(IL) ⁃ 17 family, a group of central effector cytokines of Th17 cell immune responses, plays a crucial role in host defense and inflammatory pathology, and is implicated in various immune ⁃ mediated inflammatory diseases. Recent studies have revealed that the IL ⁃ 17 family exerts more complex and significant functions in IBD. This review summarizes the research progress on the role of the IL⁃17 family in the development and progression of IBD and the potential as a therapeutic target, aiming to provide a basis for clinical decision⁃making.

关键词

炎症性肠病 / 白细胞介素⁃17 / 免疫调节 / 靶向治疗 / 溃疡性结肠炎 / 动物模型

Key words

Inflammatory Bowel Disease / Interleukin ⁃ 17 / Immune Regulation / Targeted Therapy / Ulcerative Colitis / Animal Model

参考文献

[1] LIN D P, JIN Y, SHAO X X, et al. Global, regional, and national burden of inflammatory bowel disease, 1990—2021: Insights from the global burden of disease 2021[J]. Int J Colorectal Dis, 2024, 39(1): 139.

[2] YU Z Q, RUAN G C, BAI X Y, et al. Growing burden of inflammatory bowel disease in China: Findings from the Global Burden of Disease Study 2021 and predictions to 2035[J]. Chin Med J, 2024, 137(23): 2851-2859.

[3] TEMIDO M J, HONAP S, BURSZTEJN A C, et al. Drug—induced acne in inflammatory bowel disease: A practical guide for the gastroenterologist[J]. Am J Gastroenterol, 2025, 120(1): 125-134.

[4] FUJINO S, ANDOH A, BAMBA S, et al. Increased expression of interleukin 17 in inflammatory bowel disease[J]. Gut, 2003, 52(1): 65-70.

[5] NEMETH Z H, BOGDANOVSKI D A, BARRATT—STOPPER P, et al. Crohn's disease and ulcerative colitis show unique cytokine profiles[J]. Cureus, 2017, 9(4): e1177.

[6] LUCACIU L A, ILIES M, VESA S C, et al. Serum interleukin (IL)—23 and IL—17 profile in inflammatory bowel disease (IBD) patients could differentiate between severe and non—severe disease[J]. J Pers Med, 2021, 11(11): 1130.

[7] MENESY A, HAMMAD M, AREF S, et al. Level of interleukin 17 in inflammatory bowel disease and its relation with disease activity[J]. BMC Gastroenterol, 2024, 24(1): 135.

[8] LIU B, QIAN Y, LI Y N, et al. Circulating levels of cytokines and risk of inflammatory bowel disease: Evidence from genetic data[J]. Front Immunol, 2023, 14: 1310086.

[9] MCGOVERN D P B, ROTTER J I, MEI L, et al. Genetic epistasis of IL23/IL17 pathway genes in Crohn's disease[J]. Inflamm Bowel Dis, 2009, 15(6): 883-889.

[10] ROUVIER E, LUCIANI M F, MATTÉI M G, et al. CTLA—8, cloned from an activated T cell, bearing AU—rich messenger RNA instability sequences, and homologous to a herpesvirus Saimiri gene[J]. J Immunol, 1993, 150(12): 5445-5456.

[11] JIANG X J, ZHOU R H, ZHANG Y J, et al. Interleukin—17 as a potential therapeutic target for chronic pain[J]. Front Immunol, 2022, 13: 999407.

[12] RAJ D, VERMA A K, MATHUR R, et al. Fine—tuning immunity: Ubiquitin—dependent regulation of interleukin—17A expression by Th17 cells[J]. Front Immunol, 2025, 16: 1614409.

[13] HUANG X, LI Z L, SHEN X H, et al. IL—17 upregulates MCP—1 expression via Act1/TRAF6/TAK1 in experimental autoimmune myocarditis[J]. Cytokine, 2022, 152: 155823.

[14] GHORBANI RANJBARY A, MEHRZAD J, DEHGHANI H, et al. Impact of IL—17a on apoptosis and mucinosis—related molecules in the microenvironment of colorectal cancer[J]. Arch Med Res, 2025, 56(5): 103220.

[15] DING T, ZHAO S S, GU Y H, et al. IL—17A regulates airway remodelling in COPD through the PI3K/AKT/mTOR pathway[J]. Sci Rep, 2025, 15(1): 16546.

[16] MCGEACHY M J, CUA D J, GAFFEN S L. The IL—17 family of cytokines in health and disease[J]. Immunity, 2019, 50(4): 892-906.

[17] PASTWIŃSKA J, KARWACIAK I, KARAŚ K, et al. IL—17B inhibits hepatocellular carcinoma cell proliferation[J]. Arch Immunol Ther Exp, 2025, 73(1). DOI: https://doi.org/10.2478/aite—2025—0020.

[18] MAO J Y, MA X, SUN Y Y, et al. IL—17C—mediated upregulation of SMURF2 induces psoriatic changes in keratinocytes by facilitating PPP6C ubiquitination[J]. Cell Biol Int, 2025, 49(7): 798-809.

[19] KROHN S, NIES J F, KAPFFER S, et al. IL—17C/IL—17 receptor E signaling in CD4⁺ T cells promotes T_H17 cell—driven glomerular inflammation[J]. J Am Soc Nephrol, 2018, 29(4): 1210-1222.

[20] JIANG K X, XU Y, WANG Y, et al. Deciphering the role of IL—17D, its newly identified receptor CD93, and IL—17D—CD93 axis in health and disease[J]. J Immunol, 2025, 214(6): 1113-1122.

[21] YUAN L, HUANG J L, CHEN J H, et al. Ciliated cell—derived IL—17D restrains allergic asthma through controlling monocyte recruitment[J]. J Exp Med, 2025, 222(10): e20242328.

[22] WILSON S C, CAVENEY N A, YEN M, et al. Organizing structural principles of the IL—17 ligand—receptor axis[J]. Nature, 2022, 609(7927): 622-629.

[23] SHI T, XIE Y, FU Y, et al. The signaling axis of microRNA—31/interleukin—25 regulates Th1/Th17—mediated inflammation response in colitis[J]. Mucosal Immunol, 2017, 10(4): 983-995.

[24] BOROWCZYK J, SHUTOVA M, BREMBILLA N C, et al. IL—25 (IL—17E) in epithelial immunology and pathophysiology[J]. J Allergy Clin Immunol, 2021, 148(1): 40-52.

[25] SUN T, WANG F M, LI J S, et al. ISIR and its human homolog gene AK131315 strengthen LPS—induced inflammation and acute lung injury by promoting TAK1—dependent NF—κB and MAPK signaling[J]. Int Immunopharmacol, 2024, 137: 112510.

[26] VOIGT S, STERZ K R, GIEHLER F, et al. A central role of IKK2 and TPL2 in JNK activation and viral B—cell transformation[J]. Nat Commun, 2020, 11(1): 685.

[27] TANAKA H, ARIMA Y, KAMIMURA D, et al. Phosphorylation—dependent Regnase—1 release from endoplasmic reticulum is critical in IL—17 response[J]. J Exp Med, 2019, 216(6): 1431-1449.

[28] LAYZELL S, BARBARULO A, VAN LOO G, et al. NF—κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells[J]. Cell Death Differ, 2025, 32(2): 256-270.

[29] PRESTI E L, DI MITRI R, MOCCIARO F, et al. Characterization of γδ T cells in intestinal mucosa from patients with early—onset or long—standing inflammatory bowel disease and their correlation with clinical status[J]. J Crohns Colitis, 2019, 13(7): 873-883.

[30] PRESTI E L, MOCCIARO F, MITRI R D, et al. Analysis of colon—infiltrating γδ T cells in chronic inflammatory bowel disease and in colitis—associated cancer[J]. J Leukoc Biol, 2020, 108(2): 749-760.

[31] BULEK K, LIU C N, SWAIDANI S, et al. The inducible kinase IKKi is required for IL—17—dependent signaling associated with neutrophilia and pulmonary inflammation[J]. Nat Immunol, 2011, 12(9): 844-852.

[32] YIN Q, PI X L, JIANG Y Y, et al. An immuno—blocking agent targeting IL—1β and IL—17A reduces the lesion of DSS—induced ulcerative colitis in mice[J]. Inflammation, 2021, 44(5): 1724-1736.

[33] TANG C, KAKUTA S, SHIMIZU K, et al. Suppression of IL—17F, but not of IL—17A, provides protection against colitis by inducing T_reg cells through modification of the intestinal microbiota[J]. Nat Immunol, 2018, 19(7): 755-765.

[34] DENG F H, HE S Y, CUI S D, et al. A molecular targeted immunotherapeutic strategy for ulcerative colitis via dual—targeting nanoparticles delivering miR—146b to intestinal macrophages[J]. J Crohns Colitis, 2019, 13(4): 482-494.

[35] BAI L, LI Y, LU C H, et al. Anti—IL—17 inhibits PINK1/parkin autophagy and M1 macrophage polarization in rheumatic heart disease[J]. Inflammation, 2025, 48(2): 870-884.

[36] WANG S Y, CAI L K, MA Y Y, et al. Shaoyao decoction alleviates DSS—induced colitis by inhibiting IL—17a—mediated polarization of M1 macrophages[J]. J Ethnopharmacol, 2025, 337(Pt 3): 118941.

[37] WEN Y H, CHEN Q L, WANG H, et al. Contribution of IL—17C—mediated macrophage polarization to Type 17 inflammation in neutrophilic asthma[J]. Cell Commun Signal, 2024, 22(1): 557.

[38] LATELLA G, VISCIDO A. Controversial contribution of Th17/IL—17 toward the immune response in intestinal fibrosis[J]. Dig Dis Sci, 2020, 65(5): 1299-1306.

[39] LI J, LIU L, ZHAO Q, et al. Role of interleukin—17 in pathogenesis of intestinal fibrosis in mice[J]. Dig Dis Sci, 2020, 65(7): 1971-1979.

[40] ZHANG H J, ZHANG Y N, ZHOU H, et al. IL—17A promotes initiation and development of intestinal fibrosis through EMT[J]. Dig Dis Sci, 2018, 63(11): 2898-2909.

[41] BIANCHERI P, PENDER S L, AMMOSCATO F, et al. The role of interleukin 17 in Crohn's disease—associated intestinal fibrosis[J]. Fibrogenesis Tissue Repair, 2013, 6(1): 13.

[42] DUPRAZ L, MAGNIEZ A, ROLHION N, et al. Gut microbiota—derived short—chain fatty acids regulate IL—17 production by mouse and human intestinal γδ T cells[J]. Cell Rep, 2021, 36(1): 109332.

[43] PAIK D, YAO L N, ZHANG Y C, et al. Human gut bacteria produce Τ_Η17—modulating bile acid metabolites[J]. Nature, 2022, 603(7903): 907-912.

[44] LI N, MA P G, LI Y L, et al. Gut microbiota—derived 12—ketolithocholic acid suppresses the IL—17A secretion from colonic group 3 innate lymphoid cells to prevent the acute exacerbation of ulcerative colitis[J]. Gut Microbes, 2023, 15(2): 2290315.

[45] GUO M Y, LIU H J, YU Y T, et al. Lactobacillus rhamnosus GG ameliorates osteoporosis in ovariectomized rats by regulating the Th17/Treg balance and gut microbiota structure[J]. Gut Microbes, 2023, 15(1): 2190304.

[46] BRABEC T, VOBOŘIL M, SCHIEROVÁ D, et al. IL—17—driven induction of Paneth cell antimicrobial functions protects the host from microbiota dysbiosis and inflammation in the ileum[J]. Mucosal Immunol, 2023, 16(4): 373-385.

[47] ZHU L Q, WU Z H, ZHU C, et al. The deletion of IL—17A enhances Helicobacter hepaticus colonization and triggers colitis[J]. J Inflamm Res, 2022, 15: 2761-2773.

[48] REYNOLDS J M, MARTINEZ G J, NALLAPARAJU K C, et al. Cutting edge: Regulation of intestinal inflammation and barrier function by IL—17C[J]. J Immunol, 2012, 189(9): 4226-4230.

[49] MATSUNAGA Y, CLARK T, WANEK A G, et al. Intestinal IL—17R signaling controls secretory IgA and oxidase balance in Citrobacter rodentium infection[J]. J Immunol, 2021, 206(4): 766-775.

[50] DENG Z Z, WANG S F, WU C F, et al. IL—17 inhibitor—associated inflammatory bowel disease: A study based on literature and database analysis[J]. Front Pharmacol, 2023, 14: 1124628.

[51] PETITPAIN N, D'AMICO F, YELEHE—OKOUMA M, et al. IL—17 inhibitors and inflammatory bowel diseases: A postmarketing study in vigibase[J]. Clin Pharmacol Ther, 2021, 110(1): 159-168.

[52] BURISCH J, EIGNER W, SCHREIBER S, et al. Risk for development of inflammatory bowel disease under inhibition of interleukin 17: A systematic review and meta—analysis[J]. PLoS One, 2020, 15(5): e0233781.

[53] TRUONG S L, CHIN J, LIEW D F L, et al. Systematic review and meta—analysis of inflammatory bowel disease adverse events with anti—interleukin 17A agents and tumor necrosis factor inhibitors in rheumatic disease and skin psoriasis[J]. Rheumatol Ther, 2021, 8(4): 1603-1616.

[54] FIELDHOUSE K A, UKAIBE S, CROWLEY E L, et al. Inflammatory bowel disease in patients with psoriasis treated with interleukin—17 inhibitors[J]. Drugs Context, 2020, 9: 2020—2022—1.

[55] FAUNY M, MOULIN D, D'AMICO F, et al. Paradoxical gastrointestinal effects of interleukin—17 blockers[J]. Ann Rheum Dis, 2020, 79(9): 1132-1138.

[56] CHEN J, MA H, LIU Z H, et al. Discovery of orally available retinoic acid receptor—related orphan receptor γ—t/dihydroorotate dehydrogenase dual inhibitors for the treatment of refractory inflammatory bowel disease[J]. J Med Chem, 2022, 65(1): 592-615.

[57] ZHAO H R, WANG Q, ZHAO J, et al. Ento—a alleviates DSS—induced experimental colitis in mice by remodeling intestinal microbiota to regulate SCFAs metabolism and the Th17 signaling pathway[J]. Biomed Pharmacother, 2024, 170: 115985.

[58] PAN D J, HUANG B Y, GAN Y M, et al. Phycocyanin ameliorates colitis—associated colorectal cancer by regulating the gut microbiota and the IL—17 signaling pathway[J]. Mar Drugs, 2022, 20(4): 260.

[59] WANG J, JIA Y Z, XIA N, et al. Rosemary essential oil microemulsion prevents DSS—induced intestinal injury in mice by modulating IL—17 signaling pathway[J]. J Funct Foods, 2024, 116: 106180.

[60] ZHANG S L, LI Y W, CHEN G, et al. Sarcandra glabra (Thunb.) Nakai alleviates DSS—induced ulcerative colitis by promoting restitution, restoring barrier function, and modulating IL—17/Notch1/FoxP3 pathway in intestinal cells[J]. J Ethnopharmacol, 2024, 328: 118131.

[61] LI X J, LING Y H, HUANG X Y, et al. Rosa roxburghii tratt fruit extract prevents dss—induced ulcerative colitis in mice by modulating the gut microbiota and the IL—17 signaling pathway[J]. Nutrients, 2023, 15(21): 4560.

[62] LIANG J, DAI W G, LIU C H, et al. Gingerenone A attenuates ulcerative colitis via targeting IL—17RA to inhibit inflammation and restore intestinal barrier function[J]. Adv Sci, 2024, 11(28): e2400206.

[63] CHANG S H, PARK H, DONG C. Act1 adaptor protein is an immediate and essential signaling component of interleukin—17 receptor[J]. J Biol Chem, 2006, 281(47): 35603-35607.

[64] OLIVEIRA R G, DAMAZO A S, ANTONIELLI L F, et al. Dilodendron bipinnatum Radlk. extract alleviates ulcerative colitis induced by TNBS in rats by reducing inflammatory cell infiltration, TNF—α and IL—1β concentrations, IL—17 and COX—2 expressions, supporting mucus production and promotes an antioxidant effect[J]. J Ethnopharmacol, 2021, 269: 113735.

[65] REN T Y, FENG H, XU Y, et al. Revealing the mechanism of Dahuang Huanglian Xiexin Decoction attenuates dysbiosisvia IL—17 signaling pathway based on network pharmacology and experimental validation[J]. J Ethnopharmacol, 2024, 331: 118267.

[66] 张紫凝, 杨子, 张文静, 等 . 连翘脂素通过抑制 IL—17 信号改善 2, 4, 6—三硝基苯磺酸诱导的小鼠克罗恩病样结肠炎[J]. 蚌埠医学院学报, 2023, 48(8): 1013-1017.

[67] ZHANG Z N, YANG Z, ZHANG W J, et al. Phillygenin alleviated 2, 4, 6—trinitrobenzene sulfonic acid—induced Crohn's disease—like colitis by inhibiting IL—17 signaling[J]. J Bengbu Med Coll, 2023, 48(8): 1013-1017.

[68] SAVIANO A, MANOSOUR A A, RAUCCI F, et al. New biologic (ab—IPL—IL—17) for IL—17—mediated diseases: Identification of the bioactive sequence (nIL—17) for IL—17A/F function[J]. Ann Rheum Dis, 2023, 82(11): 1415-1428.

基金资助

湖北省自然科学基金资助项目(2024AFB1073)