Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's disease (CD) and ulcerative colitis (UC); however, the cause and specific pathogenesis of IBD is yet incompletely understood. Multiple cytokines produced by different immune cell types results in complex functional networks that constitute a highly regulated messaging network of signaling pathways. Applying biological mechanisms underlying IBD at the single omic level, technologies and genetic engineering enable the quantification of the pattern of released cytokines and new insights into the cytokine landscape of IBD. We focus on the existing literature dealing with the biology of pro- or anti-inflammatory cytokines and interactions that facilitate cell-based modulation of the immune system for IBD inflammation. We summarize the main roles of substantial cytokines in IBD related to homeostatic tissue functions and the remodeling of cytokine networks in IBD, which may be specifically valuable for successful cytokine-targeted therapies via marketed products. Cytokines and their receptors are validated targets for multiple therapeutic areas, we review the current strategies for therapeutic intervention and developing cytokine-targeted therapies. New biologics have shown efficacy in the last few decades for the management of IBD; unfortunately, many patients are nonresponsive or develop therapy resistance over time, creating a need for novel therapeutics. Thus, the treatment options for IBD beyond the immune-modifying anti-TNF agents or combination therapies are expanding rapidly. Further studies are needed to fully understand the immune response, networks of cytokines, and the direct pathogenetic relevance regarding individually tailored, safe and efficient targeted-biotherapeutics.

Departments of Pediatrics Faculty Hospital Faculty of Medicine in Pilsen Charles University of Prague 323 00 Pilsen Czech Republic

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Sýkora J., Pomahačová R., Kreslová M., Cvalínová D., Štych P., Schwarz J. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J. Gastroenterol. 2018;24:2741–2763. doi: 10.3748/wjg.v24.i25.2741. PubMed DOI PMC

Kuenzig M.E., Fung S.G., Marderfeld L., Mak J.W., Kaplan G.G., Ng S.C., Wilson D.C., Cameron F., Henderson P., Kotze P.G., et al. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology. 2022;162:1147–1159.e4. doi: 10.1053/j.gastro.2021.12.282. PubMed DOI

Seyedian S.S., Nokhostin F., Malamir M.D. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J. Med. Life. 2019;12:113–122. doi: 10.25122/jml-2018-0075. PubMed DOI PMC

Cai Z., Wang S., Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front. Med. 2021;8:2681. doi: 10.3389/fmed.2021.765474. PubMed DOI PMC

Wang Y., Huang B., Jin T., Ocansey D.K.W., Jiang J., Mao F. Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy. Front. Immunol. 2022;13:835005. doi: 10.3389/fimmu.2022.835005. PubMed DOI PMC

Li X., Zhang M., Zhou G., Xie Z., Wang Y., Han J., Li L., Wu Q., Zhang S. Role of Rho GTPases in inflammatory bowel disease. Cell Death Discov. 2023;9:1–13. doi: 10.1038/s41420-023-01329-w. PubMed DOI PMC

Dotan I., Allez M., Danese S., Keir M., Tole S., McBride J. The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti-integrin therapies. Med. Res. Rev. 2020;40:245–262. doi: 10.1002/med.21601. PubMed DOI PMC

Ananthakrishnan A.N., Bernstein C.N., Iliopoulos D., Macpherson A., Neurath M.F., Ali R.A.R., Vavricka S.R., Fiocchi C. Environmental triggers in IBD: A review of progress and evidence. Nat. Rev. Gastroenterol. Hepatol. 2018;15:39–49. doi: 10.1038/nrgastro.2017.136. PubMed DOI

Bevivino G., Monteleone G. Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 2018;12:907–915. doi: 10.1080/17474124.2018.1503053. PubMed DOI

Jaeger N., Gamini R., Cella M., Schettini J.L., Bugatti M., Zhao S., Rosadini C.V., Esaulova E., Di Luccia B., Kinnett B., et al. Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat. Commun. 2021;12:1921. doi: 10.1038/s41467-021-22164-6. PubMed DOI PMC

Shen X., Kellogg R., Panyard D.J., Bararpour N., Castillo K.E., Lee-McMullen B., Delfarah A., Ubellacker J., Ahadi S., Rosenberg-Hasson Y., et al. Multi-omics microsampling for the profiling of lifestyle-associated changes in health. Nat. Biomed. Eng. 2023. Online ahead of print . PubMed DOI PMC

Liu X.Y., Tang H., Zhou Q.-Y., Zeng Y.-L., Chen D., Xu H., Li Y., Tan B., Qian J.-M. Advancing the precision management of inflammatory bowel disease in the era of omics approaches and new technology. World J. Gastroenterol. 2023;29:272. doi: 10.3748/wjg.v29.i2.272. PubMed DOI PMC

Bakker O.B., Aguirre-Gamboa R., Sanna S., Oosting M., Smeekens S.P., Jaeger M., Zorro M., Võsa U., Withoff S., Netea-Maier R.T., et al. Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses. Nat. Immunol. 2018;19:776–786. doi: 10.1038/s41590-018-0121-3. PubMed DOI PMC

Jostins L., Ripke S., Weersma R.K., Duerr R.H., McGovern D.P., Hui K.Y., Lee J.C., Schumm L.P., Sharma Y., Anderson C.A., et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124. doi: 10.1038/nature11582. PubMed DOI PMC

Neurath M.F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 2014;14:329–342. doi: 10.1038/nri3661. PubMed DOI

Negroni A., Pierdomenico M., Cucchiara S., Stronati L. NOD2 and inflammation: Current insights. J. Inflamm. Res. 2018;11:49–60. doi: 10.2147/JIR.S137606. PubMed DOI PMC

Horowitz J.E., Warner N., Staples J., Crowley E., Gosalia N., Murchie R., Van Hout C., Fiedler K., Welch G., King A.K., et al. Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease. Sci. Rep. 2021;11:5595. doi: 10.1038/s41598-021-84938-8. PubMed DOI PMC

Schett G., Elewaut D., McInnes I.B., Dayer J.M., Neurath M.F. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat. Med. 2013;19:822–824. doi: 10.1038/nm.3260. PubMed DOI

Marafini I., Sedda S., Dinallo V., Monteleone G. Inflammatory cytokines: From discoveries to therapies in IBD. Expert Opin. Biol. Ther. 2019;19:1207–1217. doi: 10.1080/14712598.2019.1652267. PubMed DOI

Xu H., Lin S., Zhou Z., Li D., Zhang X., Yu M., Zhao R., Wang Y., Qian J., Li X., et al. New genetic and epigenetic insights into the chemokine system: The latest discoveries aiding progression toward precision medicine. Cell. Mol. Immunol. 2023;20:739–776. doi: 10.1038/s41423-023-01032-x. PubMed DOI PMC

Hafler D.A. Cytokines and interventional immunology. Nat. Rev. Immunol. 2007;7:423–424. doi: 10.1038/nri2101. DOI

Cytokine Network & NETs—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/29687771/

Kany S., Vollrath J.T., Relja B. Cytokines in Inflammatory Disease. Int. J. Mol. Sci. 2019;20:6008. doi: 10.3390/ijms20236008. PubMed DOI PMC

Friedrich M., Pohin M., Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity. 2019;50:992–1006. doi: 10.1016/j.immuni.2019.03.017. PubMed DOI

Hirten R.P., Iacucci M., Shah S., Ghosh S., Colombel J.F. Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders. Clin. Gastroenterol. Hepatol. 2018;16:1374–1384. PubMed

Deckers J., Anbergen T., Hokke A.M., de Dreu A., Schrijver D.P., de Bruin K., Toner Y.C., Beldman T.J., Spangler J.B., de Greef T.F.A., et al. Engineering cytokine therapeutics. Nat. Rev. Bioeng. 2023;4:286–303. doi: 10.1038/s44222-023-00030-y. PubMed DOI PMC

Zhang J.M., An J. Cytokines, inflammation, and pain. Int. Anesthesiol. Clin. 2007;45:27–37. doi: 10.1097/AIA.0b013e318034194e. PubMed DOI PMC

Tayal V., Kalra B.S. Cytokines and anti-cytokines as therapeutics—An update. Eur. J. Pharmacol. 2008;579:1–12. doi: 10.1016/j.ejphar.2007.10.049. PubMed DOI

Danese S. New therapies for inflammatory bowel disease: From the bench to the bedside. Gut. 2012;61:918–932. doi: 10.1136/gutjnl-2011-300904. PubMed DOI

Becher B., Spath S., Goverman J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol. 2017;17:49–59. doi: 10.1038/nri.2016.123. PubMed DOI

Saxton R.A., Glassman C.R., Garcia K.C. Emerging principles of cytokine pharmacology and therapeutics. Nat. Rev. Drug Discov. 2023;22:21–37. doi: 10.1038/s41573-022-00557-6. PubMed DOI PMC

Abraham C., Abreu M.T., Turner J.R. Pattern Recognition Receptor Signaling and Cytokine Networks in Microbial Defenses and Regulation of Intestinal Barriers: Implications for Inflammatory Bowel Disease. Gastroenterology. 2022;162:1602–1616.e6. doi: 10.1053/j.gastro.2021.12.288. PubMed DOI PMC

Kagnoff M.F. The intestinal epithelium is an integral component of a communications network. J. Clin. Investig. 2014;124:2841. doi: 10.1172/JCI75225. PubMed DOI PMC

Kupsa T., Milos Horacek J., Jebavy L. The role of cytokines in acute myeloid leukemia: A systematic review. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czechoslov. 2012;156:291–301. doi: 10.5507/bp.2012.108. PubMed DOI

Chelakkot C., Ghim J., Ryu S.H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp. Mol. Med. 2018;50:1–9. doi: 10.1038/s12276-018-0126-x. PubMed DOI PMC

Mehandru S., Colombel J.F. The intestinal barrier, an arbitrator turned provocateur in IBD. Nat. Rev. Gastroenterol. Hepatol. 2021;18:83–84. doi: 10.1038/s41575-020-00399-w. PubMed DOI

Akira S., Takeda K. Toll-like receptor signalling. Nat. Rev. Immunol. 2004;4:499–511. doi: 10.1038/nri1391. PubMed DOI

Zhao J., Lu Q., Liu Y., Shi Z., Hu L., Zeng Z., Tu Y., Xiao Z., Xu Q. Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies. J. Immunol. Res. 2021;2021:8816041. doi: 10.1155/2021/8816041. PubMed DOI PMC

Yan J.B., Luo M.M., Chen Z.Y., He B.H. The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. J. Immunol. Res. 2020;2020:8813558. PubMed PMC

Mahapatro M., Erkert L., Becker C. Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut. Cells. 2021;10:111. doi: 10.3390/cells10010111. PubMed DOI PMC

Meyer F., Wendling D., Demougeot C., Prati C., Verhoeven F. Cytokines and intestinal epithelial permeability: A systematic review. Autoimmun. Rev. 2023;22:103331. doi: 10.1016/j.autrev.2023.103331. PubMed DOI

Eri R., Chieppa M. Messages from the Inside. The Dynamic Environment that Favors Intestinal Homeostasis. Front. Immunol. 2013;4:323. doi: 10.3389/fimmu.2013.00323. PubMed DOI PMC

Rescigno M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol. 2011;32:256–264. doi: 10.1016/j.it.2011.04.003. PubMed DOI

Nowarski R., Jackson R., Gagliani N., De Zoete M.R., Palm N.W., Bailis W., Low J.S., Harman C.C.D., Graham M., Elinav E., et al. Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis. Cell. 2015;163:1444–1456. doi: 10.1016/j.cell.2015.10.072. PubMed DOI PMC

Schoultz I., Keita Å.V. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells. 2020;9:1909. doi: 10.3390/cells9081909. PubMed DOI PMC

D’Incà R., Di Leo V., Corrao G., Martines D., D’Odorico A., Mestriner C., Venturi C., Longo G., Sturniolo G.C. Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am. J. Gastroenterol. 1999;94:2956–2960. doi: 10.1111/j.1572-0241.1999.01444.x. PubMed DOI

Crawford C.K., Cervantes V.L., Quilici M.L., Armién A.G., Questa M., Matloob M.S., Huynh L.D., Beltran A., Karchemskiy S.J., Crakes K.R., et al. Inflammatory cytokines directly disrupt the bovine intestinal epithelial barrier. Sci Rep. 2022;12:14578. doi: 10.1038/s41598-022-18771-y. PubMed DOI PMC

Marchiando A.M., Shen L., Graham W.V., Weber C.R., Schwarz B.T., Austin J.R., Raleigh D.R., Guan Y., Watson A.J., Montrose M.H., et al. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J. Cell Biol. 2010;189:111–126. doi: 10.1083/jcb.200902153. PubMed DOI PMC

Li X., Bechara R., Zhao J., McGeachy M.J., Gaffen S.L. IL-17 receptor-based signaling and implications for disease. Nat. Immunol. 2019;20:1594–1602. doi: 10.1038/s41590-019-0514-y. PubMed DOI PMC

Lee J.S., Tato C.M., Joyce-Shaikh B., Gulen M.F., Cayatte C., Chen Y., Blumenschein W.M., Judo M., Ayanoglu G., McClanahan T.K., et al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity. 2015;43:727–738. doi: 10.1016/j.immuni.2015.09.003. PubMed DOI PMC

Kuhn K.A., Schulz H.M., Regner E.H., Severs E.L., Hendrickson J.D., Mehta G., Whitney A.K., Ir D., Ohri N., E Robertson C., et al. Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol. 2018;11:357–368. doi: 10.1038/mi.2017.55. PubMed DOI PMC

Weigmann B., Neurath M.F. Th9 cells in inflammatory bowel diseases. Semin. Immunopathol. 2017;39:89–95. doi: 10.1007/s00281-016-0603-z. PubMed DOI

Maloy K.J., Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474:298–306. doi: 10.1038/nature10208. PubMed DOI

Liu H., Dasgupta S., Fu Y., Bailey B., Roy C., Lightcap E., Faustin B. Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD. BMC Immunol. 2019;20:42. doi: 10.1186/s12865-019-0322-z. PubMed DOI PMC

Chapuy L., Bsat M., Rubio M., Harvey F., Motta V., Schwenter F., Wassef R., Richard C., Deslandres C., Nguyen B.N., et al. Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes Reveal Differences Between Ulcerative Colitis and Crohn’s Disease. J. Crohn’s Colitis. 2020;14:393–405. doi: 10.1093/ecco-jcc/jjz156. PubMed DOI PMC

Chapuy L., Bsat M., Rubio M., Sarkizova S., Therrien A., Bouin M., Orlicka K., Weber A., Soucy G., Villani A.-C., et al. IL-12 and Mucosal CD14+ Monocyte-Like Cells Induce IL-8 in Colonic Memory CD4+ T Cells of Patients With Ulcerative Colitis but not Crohn’s Disease. J. Crohn’s Colitis. 2020;14:79–95. doi: 10.1093/ecco-jcc/jjz115. PubMed DOI PMC

Globig A.M., Hennecke N., Martin B., Seidl M., Ruf G., Hasselblatt P., Thimme R., Bengsch B. Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-γ+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm. Bowel Dis. 2014;20:2321–2329. doi: 10.1097/MIB.0000000000000210. PubMed DOI

Cətanə C.S., Neagoe I.B., Cozma V., Magdaş C., Tăbăran F., Dumitraşcu D.L. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. WJG. 2015;21:5823. PubMed PMC

Bamias G., Cominelli F. Cytokines and intestinal inflammation. Curr. Opin. Gastroenterol. 2016;32:437–442. doi: 10.1097/MOG.0000000000000315. PubMed DOI

Kinchen J., Chen H.H., Parikh K., Antanaviciute A., Jagielowicz M., Fawkner-Corbett D., Ashley N., Cubitt L., Mellado-Gomez E., Attar M., et al. Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease. Cell. 2018;175:372–386.e17. doi: 10.1016/j.cell.2018.08.067. PubMed DOI PMC

Leppkes M., Neurath M.F. Cytokines in inflammatory bowel diseases—Update 2020. Pharmacol. Res. 2020;158:104835. doi: 10.1016/j.phrs.2020.104835. PubMed DOI

Palomo J., Dietrich D., Martin P., Palmer G., Gabay C. The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine. 2015;76:25–37. doi: 10.1016/j.cyto.2015.06.017. PubMed DOI

Oshima T., Miwa H. Gastrointestinal mucosal barrier function and diseases. J. Gastroenterol. 2016;51:768–778. doi: 10.1007/s00535-016-1207-z. PubMed DOI

De Souza H.S.P., Fiocchi C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016;13:13–27. doi: 10.1038/nrgastro.2015.186. PubMed DOI

Lutter L., Hoytema van Konijnenburg D.P., Brand E.C., Oldenburg B., van Wijk F. The elusive case of human intraepithelial T cells in gut homeostasis and inflammation. Nat. Rev. Gastroenterol. Hepatol. 2018;15:637–649. doi: 10.1038/s41575-018-0039-0. PubMed DOI

Imam T., Park S., Kaplan M.H., Olson M.R. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front. Immunol. 2018;9:1212. doi: 10.3389/fimmu.2018.01212. PubMed DOI PMC

Gomez-Bris R., Saez A., Herrero-Fernandez B., Rius C., Sanchez-Martinez H., Gonzalez-Granado J.M. CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease. Int. J. Mol. Sci. 2023;24:2696. doi: 10.3390/ijms24032696. PubMed DOI PMC

Nurieva R.I., Chung Y., Martinez G.J., Yang X.O., Tanaka S., Matskevitch T.D., Wang Y.-H., Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001–1005. doi: 10.1126/science.1176676. PubMed DOI PMC

Hou G., Bishu S. Th17 Cells in Inflammatory Bowel Disease: An Update for the Clinician. Inflamm. Bowel Dis. 2020;26:653–661. doi: 10.1093/ibd/izz316. PubMed DOI PMC

Saravia J., Chapman N.M., Chi H. Helper T cell differentiation. Cell. Mol. Immunol. 2019;16:634–643. doi: 10.1038/s41423-019-0220-6. PubMed DOI PMC

Torres J., Mehandru S., Colombel J.F., Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389:1741–1755. doi: 10.1016/S0140-6736(16)31711-1. PubMed DOI

Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133. doi: 10.1016/j.cell.2006.07.035. PubMed DOI

Manel N., Unutmaz D., Littman D.R. The differentiation of human TH-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 2008;9:641–649. doi: 10.1038/ni.1610. PubMed DOI PMC

Ahern P.P., Izcue A., Maloy K.J., Powrie F. The interleukin-23 axis in intestinal inflammation. Immunol. Rev. 2008;226:147–159. doi: 10.1111/j.1600-065X.2008.00705.x. PubMed DOI

Zhou L., Ivanov I.I., Spolski R., Min R., Shenderov K., Egawa T., Levy D.E., Leonard W.J., Littman D.R. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 2007;8:967–974. doi: 10.1038/ni1488. PubMed DOI

Seder R.A., Paul W.E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. PubMed DOI

Strober W., Fuss I.J. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1756–1767.e1. doi: 10.1053/j.gastro.2011.02.016. PubMed DOI PMC

Leal R.F., Planell N., Kajekar R., Lozano J.J., Ordás I., Dotti I., Esteller M., Masamunt M.C., Parmar H., Ricart E., et al. Identification of inflammatory mediators in patients with Crohn’s disease unresponsive to anti-TNFα therapy. Gut. 2015;64:233–242. doi: 10.1136/gutjnl-2013-306518. PubMed DOI

Maggi L., Santarlasci V., Capone M., Peired A., Frosali F., Crome S.Q., Querci V., Fambrini M., Liotta F., Levings M.K., et al. CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur. J. Immunol. 2010;40:2174–2181. doi: 10.1002/eji.200940257. PubMed DOI

Ueno A., Jeffery L., Kobayashi T., Hibi T., Ghosh S., Jijon H. Th17 plasticity and its relevance to inflammatory bowel disease. J. Autoimmun. 2018;87:38–49. doi: 10.1016/j.jaut.2017.12.004. PubMed DOI

Fu S.H., Chien M.W., Hsu C.Y., Liu Y.W., Sytwu H.K. Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease. Int. J. Mol. Sci. 2020;21:3379. doi: 10.3390/ijms21093379. PubMed DOI PMC

Van Den Broek T., Borghans JA M., Van Wijk F. The full spectrum of human naive T cells. Nat. Rev. Immunol. 2018;18:363–373. doi: 10.1038/s41577-018-0001-y. PubMed DOI

Hu X., Li J., Fu M., Zhao X., Wang W. The JAK/STAT signaling pathway: From bench to clinic. Signal Transduct. Target. Ther. 2021;6:402. doi: 10.1038/s41392-021-00791-1. PubMed DOI PMC

Roy S., Rizvi Z.A., Awasthi A. Metabolic Checkpoints in Differentiation of Helper T Cells in Tissue Inflammation. Front. Immunol. 2019;9:3036. doi: 10.3389/fimmu.2018.03036. PubMed DOI PMC

White J.T., Cross E.W., Kedl R.M. Antigen-inexperienced memory CD8+ T cells: Where they come from and why we need them. Nat. Rev. Immunol. 2017;17:391–400. doi: 10.1038/nri.2017.34. PubMed DOI PMC

Papadopoulos A.O., Ndhlovu Z.M. Editing naive CD4+ T cells. Nat. Methods. 2022;19:36–37. doi: 10.1038/s41592-021-01332-y. PubMed DOI

Goswami T.K., Singh M., Dhawan M., Mitra S., Bin Emran T., Rabaan A.A., Al Mutair A., Al Alawi Z., Alhumaid S., Dhama K. Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders—Advances and challenges. Hum. Vaccines Immunother. 2022;18:2035117. doi: 10.1080/21645515.2022.2035117. PubMed DOI PMC

Jacobse J., Li J., Rings EH H.M., Samsom J.N., Goettel J.A. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front. Immunol. 2021;12:716499. doi: 10.3389/fimmu.2021.716499. PubMed DOI PMC

Lee J., Lozano-Ruiz B., Yang F.M., Fan D.D., Shen L., González-Navajas J.M. The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy. Front. Immunol. 2021;12:625667. doi: 10.3389/fimmu.2021.625667. PubMed DOI PMC

Sarra M., Pallone F., MacDonald T.T., Monteleone G. IL-23/IL-17 axis in IBD. Inflamm. Bowel Dis. 2010;16:1808–1813. doi: 10.1002/ibd.21248. PubMed DOI

Iacomino G., Aufiero V.R., Iannaccone N., Melina R., Giardullo N., De Chiara G., Venezia A., Taccone F.S., Iaquinto G., Mazzarella G. IBD: Role of intestinal compartments in the mucosal immune response. Immunobiology. 2020;225:151849. doi: 10.1016/j.imbio.2019.09.008. PubMed DOI

Veldhoen M., Hocking R.J., Atkins C.J., Locksley R.M., Stockinger B. TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells. Immunity. 2006;24:179–189. doi: 10.1016/j.immuni.2006.01.001. PubMed DOI

Fujino S., Andoh A., Bamba S., Ogawa A., Hata K., Araki Y., Bamba T., Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70. doi: 10.1136/gut.52.1.65. PubMed DOI PMC

Hölttä V., Klemetti P., Sipponen T., Westerholm-Ormio M., Kociubinski G., Salo H., Räsänen L., Kolho K.-L., Färkkilä M., Savilahti E., et al. IL-23/IL-17 immunity as a hallmark of Crohn’s disease. Inflamm. Bowel Dis. 2008;14:1175–1184. doi: 10.1002/ibd.20475. PubMed DOI

Jiang W., Su J., Zhang X., Cheng X., Zhou J., Shi R., Zhang H. Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease. Inflamm. Res. 2014;63:943–950. doi: 10.1007/s00011-014-0768-7. PubMed DOI

Ruiz de Morales J.M.G., Puig L., Daudén E., Cañete J.D., Pablos J.L., Martín A.O., Juanatey C.G., Adán A., Montalbán X., Borruel N., et al. Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies. Autoimmun. Rev. 2020;19:102429. doi: 10.1016/j.autrev.2019.102429. PubMed DOI

Durant L., Watford W.T., Ramos H.L., Laurence A., Vahedi G., Wei L., Takahashi H., Sun H.-W., Kanno Y., Powrie F., et al. Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis. Immunity. 2010;32:605–615. doi: 10.1016/j.immuni.2010.05.003. PubMed DOI PMC

(PDF) Tissue Infiltrating Lymphocytes: The Role of Cytokines in Their Growth and Differentiation. [(accessed on 21 November 2023)]. Available online: https://www.researchgate.net/publication/46287646_Tissue_infiltrating_lymphocytes_the_role_of_cytokines_in_their_growth_and_differentiation.

Ma Y.H., Zhang J., Chen X., Xie Y.-F., Pang Y.-H., Liu X.-J. Increased CD4+CD45RA−FoxP3low cells alter the balance between Treg and Th17 cells in colitis mice. World J. Gastroenterol. 2016;22:9356. doi: 10.3748/wjg.v22.i42.9356. PubMed DOI PMC

Long Y., Zhao X., Xia C., Li X., Fan C., Liu C., Wang C. Upregulated IL-17A secretion and CCR6 co-expression in Treg subsets are related to the imbalance of Treg/Th17 cells in active UC patients. Scand. J. Immunol. 2020;91:e12842. doi: 10.1111/sji.12842. PubMed DOI

Long Y., Wang C., Xia C., Li X., Fan C., Zhao X., Liu C. Recovery of CD226-TIGIT+FoxP3+ and CD226-TIGIT-FoxP3+ regulatory T cells contributes to clinical remission from active stage in ulcerative colitis patients. Immunol. Lett. 2020;218:30–39. doi: 10.1016/j.imlet.2019.12.007. PubMed DOI

Mandelbaum N., Zhang L., Carasso S., Ziv T., Lifshiz-Simon S., Davidovich I., Luz I., Berinstein E., Gefen T., Cooks T., et al. Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects. NPJ Biofilms Microbiomes. 2023;9:30. doi: 10.1038/s41522-023-00400-9. PubMed DOI PMC

Wang K., Zhang H., Kugathasan S., Annese V., Bradfield J.P., Russell R.K., Sleiman P.M.A., Imielinski M., Glessner J., Hou C., et al. Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease. Am. J. Hum. Genet. 2009;84:399. doi: 10.1016/j.ajhg.2009.01.026. PubMed DOI PMC

Moschen A.R., Tilg H., Raine T. IL-12, IL-23 and IL-17 in IBD: Immunobiology and therapeutic targeting. Nat. Rev. Gastroenterol. Hepatol. 2019;16:185–196. doi: 10.1038/s41575-018-0084-8. PubMed DOI

Younis N., Zarif R., Mahfouz R. Inflammatory bowel disease: Between genetics and microbiota. Mol. Biol. Rep. 2020;47:3053–3063. doi: 10.1007/s11033-020-05318-5. PubMed DOI

Eun C.S., Mishima Y., Wohlgemuth S., Liu B., Bower M., Carroll I.M., Sartor R.B. Induction of bacterial antigen-specific colitis by a simplified human microbiota consortium in gnotobiotic interleukin-10−/− mice. Infect. Immun. 2014;82:2239–2246. doi: 10.1128/IAI.01513-13. PubMed DOI PMC

Fagerholm S.C. Integrins in Health and Disease. N. Engl. J. Med. 2022;387:1519–1521. doi: 10.1056/NEJMcibr2209679. PubMed DOI

McLean L.P., Shea-Donohue T., Cross R.K. Vedolizumab for the treatment of ulcerative colitis and Crohn’s disease. Immunotherapy. 2012;4:883–898. doi: 10.2217/imt.12.85. PubMed DOI PMC

Mousa S.A., Davis P.J. Encyclopedia of Molecular Pharmacology. Springer; Berlin/Heidelberg, Germany: 2021. Anti-integrins; pp. 174–181. DOI

Kechagia J.Z., Ivaska J., Roca-Cusachs P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 2019;20:457–473. doi: 10.1038/s41580-019-0134-2. PubMed DOI

Takada Y., Ye X., Simon S. The integrins. Genome Biol. 2007;8:215. doi: 10.1186/gb-2007-8-5-215. PubMed DOI PMC

Mezu-Ndubuisi O.J., Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr. Res. 2021;89:1619–1626. doi: 10.1038/s41390-020-01177-9. PubMed DOI PMC

Miles A., Liaskou E., Eksteen B., Lalor P.F., Adams D.H. CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am. J. Physiol. Gastrointest. Liver Physiol. 2008;294:G1257–G1267. doi: 10.1152/ajpgi.00266.2007. PubMed DOI

Habtezion A., Nguyen L.P., Hadeiba H., Butcher E.C. Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology. 2016;150:340–354. doi: 10.1053/j.gastro.2015.10.046. PubMed DOI PMC

Hassan G.S., Salti S., Mourad W. Novel Functions of Integrins as Receptors of CD154: Their Role in Inflammation and Apoptosis. Cells. 2022;11:1747. doi: 10.3390/cells11111747. PubMed DOI PMC

Tyler C.J., Guzman M., Lundborg L.R., Yeasmin S., Zgajnar N., Jedlicka P., Bamias G., Rivera-Nieves J. Antibody secreting cells are critically dependent on integrin α4β7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis. Mucosal Immunol. 2021;15:109–119. doi: 10.1038/s41385-021-00445-z. PubMed DOI PMC

Baker K.F., Isaacs J.D. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. 2018;77:175–187. doi: 10.1136/annrheumdis-2017-211555. PubMed DOI

Role of Alpha 4-Integrins in Lymphocyte Homing to Mucosal Tissues In Vivo—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/7511642/

Rivera-Nieves J., Olson T., Bamias G., Bruce A., Solga M., Knight R.F., Hoang S., Cominelli F., Ley K. L-selectin, alpha 4 beta 1, and alpha 4 beta 7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine. J. Immunol. 2005;174:2343–2352. doi: 10.4049/jimmunol.174.4.2343. PubMed DOI

Kurmaeva E., Lord J.D., Zhang S., Bao J.R., Kevil C.G., Grisham M.B., Ostanin D.V. T cell-associated α4β7 but not α4β1 integrin is required for the induction and perpetuation of chronic colitis. Mucosal Immunol. 2014;7:1354–1365. doi: 10.1038/mi.2014.22. PubMed DOI PMC

Makker J., Hommes D.W. Etrolizumab for ulcerative colitis: The new kid on the block? Expert Opin. Biol. Ther. 2016;16:567–572. doi: 10.1517/14712598.2016.1158807. PubMed DOI

Binion D.G., West G.A., Volk E.E., Drazba J.A., Ziats N.P., Petras R.E., Fiocchi C. Acquired increase in leucocyte binding by intestinal microvascular endothelium in inflammatory bowel disease. Lancet. 1998;352:1742–1746. doi: 10.1016/S0140-6736(98)05050-8. PubMed DOI

Topographic Distribution of Homing Receptors on B and T Cells in Human Gut-Associated Lymphoid Tissue: Relation of L-Selectin and Integrin Alpha 4 Beta 7 to Naive and Memory Phenotypes—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/9006335/ PubMed PMC

De Lange K.M., Moutsianas L., Lee J.C., A Lamb C., Luo Y., A Kennedy N., Jostins L., Rice D.L., Gutierrez-Achury J., Ji S.-G., et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 2017;49:256–261. doi: 10.1038/ng.3760. PubMed DOI PMC

Keir M.E., Fuh F., Ichikawa R., Acres M., Hackney J.A., Hulme G., Carey C.D., Palmer J., Jones C.J., Long A.K., et al. Regulation and Role of αE Integrin and Gut Homing Integrins in Migration and Retention of Intestinal Lymphocytes during Inflammatory Bowel Disease. J. Immunol. 2021;207:2245–2254. doi: 10.4049/jimmunol.2100220. PubMed DOI PMC

Akdis M., Aab A., Altunbulakli C., Azkur K., Costa R.A., Crameri R., Duan S., Eiwegger T., Eljaszewicz A., Ferstl R., et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J. Allergy Clin. Immunol. 2016;138:984–1010. doi: 10.1016/j.jaci.2016.06.033. PubMed DOI

Vaillant A.A.J., Qurie A. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2022. Interleukin.

Lucey D.R., Clerici M., Shearer G.M. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin. Microbiol. Rev. 1996;9:532. doi: 10.1128/CMR.9.4.532. PubMed DOI PMC

Chen M.L., Sundrud M.S. Cytokine Networks and T-Cell Subsets in Inflammatory Bowel Diseases. Inflamm. Bowel Dis. 2016;22:1157–1167. doi: 10.1097/MIB.0000000000000714. PubMed DOI PMC

Mantovani A., Dinarello C.A., Molgora M., Garlanda C. Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity. Immunity. 2019;50:778–795. doi: 10.1016/j.immuni.2019.03.012. PubMed DOI PMC

Cominelli F., Pizarro T.T. Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. Aliment. Pharmacol. Ther. 1996;10:49–53. doi: 10.1046/j.1365-2036.1996.22164020.x. PubMed DOI

Dosh R.H., Jordan-Mahy N., Sammon C., Le Maitre C. Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model. Oncotarget. 2019;10:3559–3575. doi: 10.18632/oncotarget.26894. PubMed DOI PMC

Mucosal Imbalance of IL-1 and IL-1 Receptor Antagonist in Inflammatory Bowel Disease. A Novel Mechanism of Chronic Intestinal Inflammation—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/7868909/ PubMed

Yang B., Zhang G., Elias M., Zhu Y., Wang J. The role of cytokine and immune responses in intestinal fibrosis. J. Dig. Dis. 2020;21:308–314. doi: 10.1111/1751-2980.12879. PubMed DOI

Adler J., Rahal K., Swanson S.D., Schmiedlin-Ren P., Rittershaus A.C., Reingold L.J., Brudi J.S., Shealy D., Cai A., McKenna B.J., et al. Anti-tumor necrosis factor α prevents bowel fibrosis assessed by messenger RNA, histology, and magnetization transfer MRI in rats with Crohn’s disease. Inflamm. Bowel Dis. 2013;19:683–690. doi: 10.1097/MIB.0b013e3182802c32. PubMed DOI

Voronov E., Apte R.N. IL-1 in Colon Inflammation, Colon Carcinogenesis and Invasiveness of Colon Cancer. Cancer Microenviron. 2015;8:187. doi: 10.1007/s12307-015-0177-7. PubMed DOI PMC

Mak’Anyengo R., Duewell P., Reichl C., Hörth C., Lehr H., Fischer S., Clavel T., Denk G., Hohenester S., Kobold S., et al. Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut. JCI Insight. 2018;3:e96322. doi: 10.1172/jci.insight.96322. PubMed DOI PMC

Ju J., Zhang C., Yang J., Yang Q., Yin P., Sun X. Deoxycholic acid exacerbates intestinal inflammation by modulating interleukin-1 β expression and tuft cell proportion in dextran sulfate sodium-induced murine colitis. PeerJ. 2023;11:e14842. doi: 10.7717/peerj.14842. PubMed DOI PMC

Qazi B.S., Tang K., Qazi A. Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis. Int. J. Inflamm. 2011;2011:908468. doi: 10.4061/2011/908468. PubMed DOI PMC

Matsushima K., Yang D., Oppenheim J.J. Interleukin-8: An evolving chemokine. Cytokine. 2022;153:155828. doi: 10.1016/j.cyto.2022.155828. PubMed DOI

Wu L., Ruffing N., Shi X., Newman W., Soler D., Mackay C.R., Qin S. Discrete steps in binding and signaling of interleukin-8 with its receptor. J. Biol. Chem. 1996;271:31202–31209. doi: 10.1074/jbc.271.49.31202. PubMed DOI

Ramjeesingh R., Leung R., Siu C.H. Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. FASEB J. 2003;17:1292–1294. doi: 10.1096/fj.02-0560fje. PubMed DOI

Gijsbers K., Van Assche G., Joossens S., Struyf S., Proost P., Rutgeerts P., Geboes K., Van Damme J. CXCR1-binding chemokines in inflammatory bowel diseases: Down-regulated IL-8/CXCL8 production by leukocytes in Crohn’s disease and selective GCP-2/CXCL6 expression in inflamed intestinal tissue. Eur. J. Immunol. 2004;34:1992–2000. doi: 10.1002/eji.200324807. PubMed DOI

Arai F., Takahashi T., Furukawa K., Matsushima K., Asakura H. Mucosal expression of interleukin-6 and interleukin-8 messenger RNA in ulcerative colitis and in Crohn’s disease. Dig. Dis. Sci. 1998;43:2071–2079. doi: 10.1023/A:1018815432504. PubMed DOI

Increased Expression of Interleukin-8 mRNA in Ulcerative Colitis and Crohn’s Disease Mucosa and Epithelial Cells—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/23283312/ PubMed

Brandt E., Colombel J., Ectors N., Gambiez L., Emilie D., Geboes K., Capron M., Desreumaux P. Enhanced production of IL-8 in chronic but not in early ileal lesions of Crohn’s disease (CD) Clin. Exp. Immunol. 2000;122:180. doi: 10.1046/j.1365-2249.2000.01364.x. PubMed DOI PMC

Zhou H.Y., Yan J., Fang L., Zhang H., Su L.-G., Zhou G.-H. Change and significance of IL-8, IL-4, and IL-10 in the pathogenesis of terminal Ileitis in SD rat. Cell Biochem. Biophys. 2014;69:327–331. doi: 10.1007/s12013-013-9802-6. PubMed DOI

Siakavellas S.I., Bamias G. Role of the IL-23/IL-17 Axis in Crohn’s Disease. Discov. Med. 2012;14:253–262. PubMed

Mazzucchelli L., Hauser C., Zgraggen K., Wagner H., Hess M., A Laissue J., Mueller C. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am. J. Pathol. 1994;144:997. PubMed PMC

Correlation between IL-8 Gene Polymorphisms and Pathogenesis of Crohn’s Disease—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/37023312/ PubMed

Li J., Moran T., Swanson E., Julian C., Harris J., Bonen D.K., Hedl M., Nicolae D.L., Abraham C., Cho J.H. Regulation of IL-8 and IL-1beta expression in Crohn’s disease associated NOD2/CARD15 mutations. Hum. Mol. Genet. 2004;13:1715–1725. doi: 10.1093/hmg/ddh182. PubMed DOI

Su Y., Zhao H. Predisposition of Inflammatory Bowel Disease Is Influenced by IL-8, IL-10, and IL-18 Polymorphisms: A Meta-Analysis. Int. Arch. Allergy Immunol. 2020;181:799–806. doi: 10.1159/000509110. PubMed DOI

Subramanian S., Rhodes J.M., Hart A.C., Tam B., Roberts C.L., Smith S.L., Corkill J.E., Winstanley C., Virji M., Campbell B.J. Characterization of epithelial IL-8 response to inflammatory bowel disease mucosal E. coli and its inhibition by mesalamine. Inflamm. Bowel Dis. 2008;14:162. doi: 10.1002/ibd.20296. PubMed DOI PMC

Schmitt H., Neurath M.F., Atreya R. Role of the IL23/IL17 Pathway in Crohn’s Disease. Front. Immunol. 2021;12:622934. doi: 10.3389/fimmu.2021.622934. PubMed DOI PMC

Zenobia C., Hajishengallis G. Basic biology and role of interleukin-17 in immunity and inflammation. Periodontology. 2000;69:142. doi: 10.1111/prd.12083. PubMed DOI PMC

Omidian Z., Ahmed R., Giwa A., Donner T., Hamad AR A. IL-17 and limits of success. Cell. Immunol. 2019;339:33–40. doi: 10.1016/j.cellimm.2018.09.001. PubMed DOI PMC

Krawiec P., Pac-Kożuchowska E. Serum interleukin 17A and interleukin 17F in children with inflammatory bowel disease. Sci. Rep. 2020;10:12617. doi: 10.1038/s41598-020-69567-x. PubMed DOI PMC

Puel A., Cypowyj S., Bustamante J., Wright J.F., Liu L., Lim H.K., Migaud M., Israel L., Chrabieh M., Audry M., et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332:65–68. doi: 10.1126/science.1200439. PubMed DOI PMC

Chen L., Ruan G., Cheng Y., Yi A., Chen D., Wei Y. The role of Th17 cells in inflammatory bowel disease and the research progress. Front. Immunol. 2022;13:1055914. doi: 10.3389/fimmu.2022.1055914. PubMed DOI PMC

Lucaciu L.A., Ilieș M., Vesa C., Seicean R., Din S., Iuga C.A., Seicean A. Serum interleukin (Il)-23 and il-17 profile in inflammatory bowel disease (ibd) patients could differentiate between severe and non-severe disease. J. Pers. Med. 2021;11:1130. doi: 10.3390/jpm11111130. PubMed DOI PMC

Zeng B., Shi S., Ashworth G., Dong C., Liu J., Xing F. ILC3 function as a double-edged sword in inflammatory bowel diseases. Cell Death Dis. 2019;10:315. doi: 10.1038/s41419-019-1540-2. PubMed DOI PMC

Alexander M., Ang Q.Y., Nayak R.R., Bustion A.E., Sandy M., Zhang B., Upadhyay V., Pollard K.S., Lynch S.V., Turnbaugh P.J. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe. 2022;30:17–30.e9. doi: 10.1016/j.chom.2021.11.001. PubMed DOI PMC

Latella G., Viscido A. Controversial Contribution of Th17/IL-17 Toward the Immune Response in Intestinal Fibrosis. Dig. Dis. Sci. 2020;65:1299–1306. doi: 10.1007/s10620-020-06161-1. PubMed DOI

Zhang H.J., Zhang Y.-N., Zhou H., Guan L., Li Y., Sun M.-J. IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT. Dig. Dis. Sci. 2018;63:2898–2909. doi: 10.1007/s10620-018-5234-x. PubMed DOI

Qing J., Li C., Hu X., Song W., Tirichen H., Yaigoub H., Li Y. Differentiation of T Helper 17 Cells May Mediate the Abnormal Humoral Immunity in IgA Nephropathy and Inflammatory Bowel Disease Based on Shared Genetic Effects. Front. Immunol. 2022;13:916934. doi: 10.3389/fimmu.2022.916934. PubMed DOI PMC

Fieldhouse K.A., Ukaibe S., Crowley E.L., Khanna R., O’Toole A., Gooderham M.J. Inflammatory bowel disease in patients with psoriasis treated with interleukin-17 inhibitors. Drugs Context. 2020;9:2020-2-1. doi: 10.7573/dic.2020-2-1. PubMed DOI PMC

Ju J., Dai Y., Yang J., Liu C., Fan L., Feng L., Zhao B., Zeng M., Liu Z., Sun X. Crohn’s disease exacerbated by IL-17 inhibitors in patients with psoriasis: A case report. BMC Gastroenterol. 2020;20:340. doi: 10.1186/s12876-020-01474-x. PubMed DOI PMC

Holst L.M., Halfvarson J., Carlson M., Hedin C., Kruse R., Lindqvist C.M., Bergemalm D., Almér S., Bresso F., Lundström M.L., et al. Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis. Clin. Exp. Gastroenterol. 2022;15:129. doi: 10.2147/CEG.S368040. PubMed DOI PMC

Kaiko G.E., Chen F., Lai C.-W., Chiang I.-L., Perrigoue J., Stojmirović A., Li K., Muegge B.D., Jain U., VanDussen K.L., et al. PAI-1 augments mucosal damage in colitis. Sci. Transl. Med. 2019;11:eaat0852. doi: 10.1126/scitranslmed.aat0852. PubMed DOI PMC

Yasuda K., Nakanishi K., Tsutsui H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019;20:649. doi: 10.3390/ijms20030649. PubMed DOI PMC

Victor A.R., Nalin A.P., Dong W., McClory S., Wei M., Mao C., Kladney R.D., Youssef Y., Chan W.K., Briercheck E.L., et al. IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB. J. Immunol. 2017;199:2333–2342. doi: 10.4049/jimmunol.1601554. PubMed DOI PMC

Mi J., Liu Z., Pei S., Wu X., Zhao N., Jiang L., Zhang Z., Bai X. Mendelian randomization study for the roles of IL-18 and IL-1 receptor antagonist in the development of inflammatory bowel disease. Int. Immunopharmacol. 2022;110:109020. doi: 10.1016/j.intimp.2022.109020. PubMed DOI

Jarry A., Bossard C., Droy-Dupré L., Volteau C., Bourreille A., Meurette G., Mosnier J.-F., Laboisse C.L. Heterogeneity of subordination of the IL-18/IFN-γ axis to caspase-1 among patients with Crohn’s disease. Lab. Investig. 2015;95:1207–1217. doi: 10.1038/labinvest.2015.89. PubMed DOI

Pu Z., Che Y., Zhang W., Sun H., Meng T., Xie H., Cao L., Hao H. Dual roles of IL-18 in colitis through regulation of the function and quantity of goblet cells. Int. J. Mol. Med. 2019;43:2291. doi: 10.3892/ijmm.2019.4156. PubMed DOI PMC

Guan Q., Warrington R., Moreno S., Qing G., Weiss C., Peng Z. Sustained suppression of IL-18 by employing a vaccine ameliorates intestinal inflammation in TNBS-induced murine colitis. Future Sci. OA. 2019;5:FSO405. doi: 10.2144/fsoa-2018-0125. PubMed DOI PMC

Greving C.N.A., Towne J.E. A Role for IL-12 in IBD after All? Immunity. 2019;51:209–211. doi: 10.1016/j.immuni.2019.07.008. PubMed DOI

Jefremow A., Neurath M.F. All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD—A Clinical Perspective. ImmunoTargets Ther. 2020;9:289. doi: 10.2147/ITT.S282466. PubMed DOI PMC

Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 2003;3:133–146. doi: 10.1038/nri1001. PubMed DOI

Tang C., Chen S., Qian H., Huang W. Interleukin-23: As a drug target for autoimmune inflammatory diseases. Immunology. 2012;135:112. doi: 10.1111/j.1365-2567.2011.03522.x. PubMed DOI PMC

Sewell G.W., Kaser A. Interleukin-23 in the Pathogenesis of Inflammatory Bowel Disease and Implications for Therapeutic Intervention. J. Crohn’s Colitis. 2022;16:II3–II19. doi: 10.1093/ecco-jcc/jjac034. PubMed DOI PMC

Łukasik Z., Gracey E., Venken K., Ritchlin C., Elewaut D. Crossing the boundaries: IL-23 and its role in linking inflammation of the skin, gut and joints. Rheumatology. 2021;60:IV16–IV27. doi: 10.1093/rheumatology/keab385. PubMed DOI PMC

Misselwitz B., Juillerat P., Sulz M.C., Siegmund B., Brand S. Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More. Digestion. 2020;101:69–82. doi: 10.1159/000507782. PubMed DOI

Gottlieb Z.S., Sands B.E. Personalised Medicine with IL-23 Blockers: Myth or Reality? J. Crohn’s Colitis. 2022;16:II73–II94. doi: 10.1093/ecco-jcc/jjab190. PubMed DOI PMC

Valenti M., Narcisi A., Pavia G., Gargiulo L., Costanzo A. What Can IBD Specialists Learn from IL-23 Trials in Dermatology? J. Crohn’s Colitis. 2022;16:II20–II29. doi: 10.1093/ecco-jcc/jjac023. PubMed DOI PMC

Bauché D., Joyce-Shaikh B., Jain R., Grein J., Ku K.S., Blumenschein W.M., Ganal-Vonarburg S.C., Wilson D.C., McClanahan T.K., Malefyt R.d.W., et al. LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis. Immunity. 2018;49:342–352.e5. doi: 10.1016/j.immuni.2018.07.007. PubMed DOI

Aschenbrenner D., Quaranta M., Banerjee S., Ilott N., Jansen J., Steere B., Chen Y.-H., Ho S., Cox K., Arancibia-Cárcamo C.V., et al. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut. 2021;70:1023–1036. doi: 10.1136/gutjnl-2020-321731. PubMed DOI PMC

Plavec T.V., Kuchař M., Benko A., Lišková V., Černý J., Berlec A., Malý P. Engineered Lactococcus lactis Secreting IL-23 Receptor-Targeted REX Protein Blockers for Modulation of IL-23/Th17-Mediated Inflammation. Microorganisms. 2019;7:152. doi: 10.3390/microorganisms7050152. PubMed DOI PMC

Bhatt B., Zeng P., Zhu H., Sivaprakasam S., Li S., Xiao H., Dong L., Shiao P., Kolhe R., Patel N., et al. Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation. J. Immunol. 2018;200:2905. doi: 10.4049/jimmunol.1701625. PubMed DOI PMC

Eftychi C., Schwarzer R., Vlantis K., Wachsmuth L., Basic M., Wagle P., Neurath M.F., Becker C., Bleich A., Pasparakis M. Temporally Distinct Functions of the Cytokines IL-12 and IL-23 Drive Chronic Colon Inflammation in Response to Intestinal Barrier Impairment. Immunity. 2019;51:367–380.e4. doi: 10.1016/j.immuni.2019.06.008. PubMed DOI

Becker C., Wirtz S., Blessing M., Pirhonen J., Strand D., Bechthold O., Frick J., Galle P.R., Autenrieth I., Neurath M.F. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Investig. 2003;112:693–706. doi: 10.1172/JCI200317464. PubMed DOI PMC

Luo X., Villablanca E.J. Type 2 immunity in intestinal homeostasis and inflammatory bowel disease. Biochem. Soc. Trans. 2021;49:2371–2380. doi: 10.1042/BST20210535. PubMed DOI PMC

Hodzic Z., Schill E.M., Bolock A.M., Good M. IL-33 and the intestine: The good, the bad, and the inflammatory. Cytokine. 2017;100:1–10. doi: 10.1016/j.cyto.2017.06.017. PubMed DOI PMC

Aggeletopoulou I., Tsounis E.P., Triantos C. Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease. Int. J. Mol. Sci. 2022;24:623. doi: 10.3390/ijms24010623. PubMed DOI PMC

Kotsiou O.S., Gourgoulianis K.I., Zarogiannis S.G. IL-33/ST2 Axis in Organ Fibrosis. Front. Immunol. 2018;9:2432. doi: 10.3389/fimmu.2018.02432. PubMed DOI PMC

Bamias G., Pizarro T.T., Cominelli F. Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease. Inflamm. Bowel. Dis. 2022;28:337–349. doi: 10.1093/ibd/izab251. PubMed DOI PMC

He Z., Chen L., Furtado G.C., Lira S.A. Interleukin 33 regulates gene expression in intestinal epithelial cells independently of its nuclear localization. Cytokine. 2018;111:146–153. doi: 10.1016/j.cyto.2018.08.009. PubMed DOI PMC

Lopetuso L.R., De Salvo C., Pastorelli L., Rana N., Senkfor H.N., Petito V., Di Martino L., Scaldaferri F., Gasbarrini A., Cominelli F., et al. IL-33 promotes recovery from acute colitis by inducing miR-320 to stimulate epithelial restitution and repair. Proc. Natl. Acad. Sci. USA. 2018;115:E9362–E9370. doi: 10.1073/pnas.1803613115. PubMed DOI PMC

Ngo Thi Phuong N., Palmieri V., Adamczyk A., Klopfleisch R., Langhorst J., Hansen W., Westendorf A.M., Pastille E. IL-33 Drives Expansion of Type 2 Innate Lymphoid Cells and Regulatory T Cells and Protects Mice From Severe, Acute Colitis. Front. Immunol. 2021;12:669787. doi: 10.3389/fimmu.2021.669787. PubMed DOI PMC

De Salvo C., Buela K.-A., Creyns B., Corridoni D., Rana N., Wargo H.L., Cominelli C.L., Delaney P.G., Rodriguez-Palacios A., Cominelli F., et al. NOD2 drives early IL-33-dependent expansion of group 2 innate lymphoid cells during Crohn’s disease-like ileitis. J. Clin. Investig. 2021;131:e140624. doi: 10.1172/JCI140624. PubMed DOI PMC

Latiano A., Palmieri O., Pastorelli L., Vecchi M., Pizarro T.T., Bossa F., Merla G., Augello B., Latiano T., Corritore G., et al. Associations between Genetic Polymorphisms in IL-33, IL1R1 and Risk for Inflammatory Bowel Disease. PLoS ONE. 2013;8:e62144. doi: 10.1371/journal.pone.0062144. PubMed DOI PMC

Ngo V.L., Kuczma M., Maxim E., Denning T.L. IL-36 cytokines and gut immunity. Immunology. 2021;163:145–154. doi: 10.1111/imm.13310. PubMed DOI PMC

Scheibe K., Backert I., Wirtz S., Hueber A., Schett G., Vieth M., Probst H.C., Bopp T., Neurath M.F., Neufert C. IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo. Gut. 2017;66:823–838. doi: 10.1136/gutjnl-2015-310374. PubMed DOI

Scheibe K., Kersten C., Schmied A., Vieth M., Primbs T., Carlé B., Knieling F., Claussen J., Klimowicz A.C., Zheng J., et al. Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation. Gastroenterology. 2018;156:1082–1097.e11. doi: 10.1053/j.gastro.2018.11.029. PubMed DOI

Elias M., Zhao S., Le H.T., Wang J., Neurath M.F., Neufert C., Fiocchi C., Rieder F. IL-36 in chronic inflammation and fibrosis—Bridging the gap? J. Clin. Investig. 2021;131:e144336. doi: 10.1172/JCI144336. PubMed DOI PMC

De Graaf D.M., Wang R.X., Amo-Aparicio J., Lee J.S., Dowdell A.S., Tengesdal I.W., Marchetti C., Colgan S.P., Joosten L.A.B., Dinarello C.A. IL-38 Gene Deletion Worsens Murine Colitis. Front. Immunol. 2022;13:840719. doi: 10.3389/fimmu.2022.840719. PubMed DOI PMC

Xie C., Yan W., Quan R., Chen C., Tu L., Hou X., Fu Y. Interleukin-38 is elevated in inflammatory bowel diseases and suppresses intestinal inflammation. Cytokine. 2020;127:154963. doi: 10.1016/j.cyto.2019.154963. PubMed DOI

Fonseca-Camarillo G., Furuzawa-Carballeda J., Iturriaga-Goyon E., Yamamoto-Furusho J.K. Differential Expression of IL-36 Family Members and IL-38 by Immune and Nonimmune Cells in Patients with Active Inflammatory Bowel Disease. BioMed Res. Int. 2018;2018:5140691. doi: 10.1155/2018/5140691. PubMed DOI PMC

Ohno M., Imai T., Chatani M., Nishida A., Inatomi O., Kawahara M., Hoshino T., Andoh A. The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease. J. Clin. Biochem. Nutr. 2022;70:64. doi: 10.3164/jcbn.21-104. PubMed DOI PMC

Opal S.M., DePalo V.A. Anti-inflammatory cytokines. Chest. 2000;117:1162–1172. doi: 10.1378/chest.117.4.1162. PubMed DOI

Jayme T.S., Leung G., Wang A., Workentine M.L., Rajeev S., Shute A., Callejas B.E., Mancini N., Beck P.L., Panaccione R., et al. Human interleukin-4-treated regulatory macrophages promote epithelial wound healing and reduce colitis in a mouse model. Sci. Adv. 2020;6:eaba4376. doi: 10.1126/sciadv.aba4376. PubMed DOI PMC

Zhou X., Li W., Wang S., Zhang P., Wang Q., Xiao J., Zhang C., Zheng X., Xu X., Xue S., et al. YAP Aggravates Inflammatory Bowel Disease by Regulating M1/M2 Macrophage Polarization and Gut Microbial Homeostasis. Cell Rep. 2019;27:1176–1189.e5. doi: 10.1016/j.celrep.2019.03.028. PubMed DOI

Leung G., Wang A., Fernando M., Phan V.C., McKay D.M. Bone marrow-derived alternatively activated macrophages reduce colitis without promoting fibrosis: Participation of IL-10. Am. J. Physiol. Gastrointest. Liver Physiol. 2013;304:G781–G792. doi: 10.1152/ajpgi.00055.2013. PubMed DOI

Ebrahimi Daryani N., Saghazadeh A., Moossavi S., Sadr M., Shahkarami S., Soltani S., Farhadi E., Rezaei N. Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease. Immunol. Investig. 2017;46:714–729. doi: 10.1080/08820139.2017.1360343. PubMed DOI

Uciechowski P., Dempke WC M. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology. 2020;98:131–137. doi: 10.1159/000505099. PubMed DOI

Pawłowska-Kamieniak A., Krawiec P., Pac-Kożuchowska E. Interleukin 6: Biological significance and role in inflammatory bowel diseases. Adv. Clin. Exp. Med. 2021;30:465–469. doi: 10.17219/acem/130356. PubMed DOI

Ye M., Joosse M.E., Liu L., Sun Y., Dong Y., Cai C., Song Z., Zhang J., Brant S.R., Lazarev M., et al. Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice. J. Crohn’s Colitis. 2020;14:831–840. doi: 10.1093/ecco-jcc/jjz176. PubMed DOI PMC

Lu Q., Yang M.-F., Liang Y.-J., Xu J., Xu H.-M., Nie Y.-Q., Wang L.-S., Yao J., Li D.-F. Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J. Inflamm. Res. 2022;15:1825. doi: 10.2147/JIR.S353038. PubMed DOI PMC

Velikova T.V., Miteva L., Stanilov N., Spassova Z., Stanilova S.A. Interleukin-6 compared to the other Th17/Treg related cytokines in inflammatory bowel disease and colorectal cancer. World J. Gastroenterol. 2020;26:1912. doi: 10.3748/wjg.v26.i16.1912. PubMed DOI PMC

Shahini A., Shahini A. Role of interleukin-6-mediated inflammation in the pathogenesis of inflammatory bowel disease: Focus on the available therapeutic approaches and gut microbiome. J. Cell Commun. Signal. 2023;17:55. doi: 10.1007/s12079-022-00695-x. PubMed DOI PMC

Parisinos C.A., Serghiou S., Katsoulis M., George M.J., Patel R.S., Hemingway H., Hingorani A.D. Variation in Interleukin 6 Receptor Gene Associates With Risk of Crohn’s Disease and Ulcerative Colitis. Gastroenterology. 2018;155:303–306.e2. doi: 10.1053/j.gastro.2018.05.022. PubMed DOI PMC

Nayar S., Morrison J.K., Giri M., Gettler K., Chuang L.-S., Walker L.A., Ko H.M., Kenigsberg E., Kugathasan S., Merad M., et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn’s disease. Nature. 2021;593:275–281. doi: 10.1038/s41586-021-03484-5. PubMed DOI PMC

Goswami R., Kaplan M.H. A Brief History of IL-9. J. Immunol. 2011;186:3283. doi: 10.4049/jimmunol.1003049. PubMed DOI PMC

Dardalhon V., Awasthi A., Kwon H., Galileos G., Gao W., Sobel R.A., Mitsdoerffer M., Strom T.B., Elyaman W., Ho I.-C., et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3− effector T cells. Nat. Immunol. 2008;9:1347–1355. doi: 10.1038/ni.1677. PubMed DOI PMC

Defendenti C., Sarzi-Puttini P., Saibeni S., Bollani S., Bruno S., Almasio P.L., Declich P., Atzeni F. Significance of serum Il-9 levels in inflammatory bowel disease. Int. J. Immunopathol. Pharmacol. 2015;28:569–575. doi: 10.1177/0394632015600535. PubMed DOI

Gerlach K., McKenzie A.N., Neurath M.F., Weigmann B. IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis. Tissue Barriers. 2015;3:e983777. doi: 10.4161/21688370.2014.983777. PubMed DOI PMC

Stanko K., Iwert C., Appelt C., Vogt K., Schumann J., Strunk F.J., Ahrlich S., Schlickeiser S., Romagnani C., Jürchott K., et al. CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells. Proc. Natl. Acad. Sci. USA. 2018;115:E2940–E2949. doi: 10.1073/pnas.1708329115. PubMed DOI PMC

Gerlach K., Hwang Y., Nikolaev A., Atreya R., Dornhoff H., Steiner S., Lehr H.-A., Wirtz S., Vieth M., Waisman A., et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 2014;15:676–686. doi: 10.1038/ni.2920. PubMed DOI

Bird L. IL-9 breaks down barriers. Nat. Rev. Immunol. 2014;14:432. doi: 10.1038/nri3709. PubMed DOI

Vyas S.P., Goswami R. A Decade of Th9 Cells: Role of Th9 Cells in Inflammatory Bowel Disease. Front. Immunol. 2018;9:1139. doi: 10.3389/fimmu.2018.01139. PubMed DOI PMC

Matusiewicz M., Neubauer K., Bednarz-Misa I., Gorska S., Krzystek-Korpacka M. Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis. World J. Gastroenterol. 2017;23:4039. doi: 10.3748/wjg.v23.i22.4039. PubMed DOI PMC

Fiorentino D.F., Bond M.W., Mosmann T.R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 1989;170:2081–2095. doi: 10.1084/jem.170.6.2081. PubMed DOI PMC

Savan R., Ravichandran S., Collins J.R., Sakai M., Young H.A. Structural conservation of interferon gamma among vertebrates. Cytokine Growth Factor Rev. 2009;20:115–124. doi: 10.1016/j.cytogfr.2009.02.006. PubMed DOI PMC

Yang W., Liu H., Xu L., Yu T., Zhao X., Yao S., Zhao Q., Barnes S., Cohn S.M., Dann S.M., et al. GPR120 Inhibits Colitis Through Regulation of CD4+ T Cell Interleukin 10 Production. Gastroenterology. 2022;162:150–165. doi: 10.1053/j.gastro.2021.09.018. PubMed DOI PMC

Engelhardt K.R., Grimbacher B. Current Topics in Microbiology and Immunology. Volume 380. Springer; Berlin/Heidelberg, Germany: 2014. IL-10 in humans: Lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms; pp. 1–18. PubMed

Buruiana F.E., Solà I., Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2010;2010:CD005109. doi: 10.1002/14651858.CD005109.pub3. PubMed DOI PMC

Wei H.X., Wang B., Li B. IL-10 and IL-22 in Mucosal Immunity: Driving Protection and Pathology. Front. Immunol. 2020;11:1315. doi: 10.3389/fimmu.2020.01315. PubMed DOI PMC

Lv J.J., Su W., Chen X.-Y., Yu Y., Xu X., Xu C.-D., Deng X., Huang J.-B., Wang X.-Q., Xiao Y. Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease. World J. Gastroenterol. 2021;27:7705. doi: 10.3748/wjg.v27.i44.7705. PubMed DOI PMC

Ouyang W., O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: From Basic Science to Clinical Translation. Immunity. 2019;50:871–891. doi: 10.1016/j.immuni.2019.03.020. PubMed DOI

Kobayashi S., Teramura M., Oshimi K., Mizoguchi H. Interleukin-11. Leuk. Lymphoma. 2009;15:45–49. doi: 10.3109/10428199409051676. PubMed DOI

Rodríguez-Bores L., Fonseca G.C., Villeda M.A., Yamamoto-Furusho J.K. Novel genetic markers in inflammatory bowel disease. World J. Gastroenterol. WJG. 2007;13:5560. doi: 10.3748/wjg.v13.i42.5560. PubMed DOI PMC

Kiessling S., Muller-Newen G., Leeb S.N., Hausmann M., Rath H.C., Strater J., Spottl T., Schlottmann K., Grossmann J., Montero-Julian F.A., et al. Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J. Biol. Chem. 2004;279:10304–10315. doi: 10.1074/jbc.M312757200. PubMed DOI

Minty A., Chalon P., Derocq J.-M., Dumont X., Guillemot J.-C., Kaghad M., Labit C., Leplatois P., Liauzun P., Miloux B., et al. lnterleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362:248–250. doi: 10.1038/362248a0. PubMed DOI

Heller F., Fuss I.J., Nieuwenhuis E.E., Blumberg R.S., Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17:629–638. doi: 10.1016/S1074-7613(02)00453-3. PubMed DOI

Panés J., Rimola J. Perianal fistulizing Crohn’s disease: Pathogenesis, diagnosis and therapy. Nat. Rev. Gastroenterol. Hepatol. 2017;14:652–664. doi: 10.1038/nrgastro.2017.104. PubMed DOI

Kałużna A., Olczyk P., Komosińska-Vassev K. The Role of Innate and Adaptive Immune Cells in the Pathogenesis and Development of the Inflammatory Response in Ulcerative Colitis. J. Clin. Med. 2022;11:400. doi: 10.3390/jcm11020400. PubMed DOI PMC

Liu G.H., Zhuo X.-C., Huang Y.-H., Liu H.-M., Wu R.-C., Kuo C.-J., Chen N.-H., Chuang L.-P., Lin S.-W., Chen Y.-L., et al. Alterations in Gut Microbiota and Upregulations of VPAC2 and Intestinal Tight Junctions Correlate with Anti-Inflammatory Effects of Electroacupuncture in Colitis Mice with Sleep Fragmentation. Biology. 2022;11:962. doi: 10.3390/biology11070962. PubMed DOI PMC

Jovani M., Fiorino G., Danese S. Anti-IL-13 in inflammatory bowel disease: From the bench to the bedside. Curr. Drug Targets. 2013;14:1444–1452. doi: 10.2174/13894501113149990170. PubMed DOI

Dudakov J.A., Hanash A.M., Van Den Brink MR M. Interleukin-22: Immunobiology and pathology. Annu. Rev. Immunol. 2015;33:747–785. doi: 10.1146/annurev-immunol-032414-112123. PubMed DOI PMC

Andoh A., Zhang Z., Inatomi O., Fujino S., Deguchi Y., Araki Y., Tsujikawa T., Kitoh K., Kim–Mitsuyama S., Takayanagi A., et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005;129:969–984. doi: 10.1053/j.gastro.2005.06.071. PubMed DOI

Patnaude L., Mayo M., Mario R., Wu X., Knight H., Creamer K., Wilson S., Pivorunas V., Karman J., Phillips L., et al. Mechanisms and regulation of IL-22-mediated intestinal epithelial homeostasis and repair. Life Sci. 2021;271:119195. doi: 10.1016/j.lfs.2021.119195. PubMed DOI

Mizoguchi A., Yano A., Himuro H., Ezaki Y., Sadanaga T., Mizoguchi E., Yano A., Himuro H., Ezaki Y., Sadanaga T., et al. Clinical importance of IL-22 cascade in IBD. J. Gastroenterol. 2018;53:465–474. doi: 10.1007/s00535-017-1401-7. PubMed DOI PMC

Keir M.E., Yi T., Lu T.T., Ghilardi N. The role of IL-22 in intestinal health and disease. J. Exp. Med. 2020;217:e20192195. doi: 10.1084/jem.20192195. PubMed DOI PMC

Powell N., Pantazi E., Pavlidis P., Tsakmaki A., Li K., Yang F., Parker A., Pin C., Cozzetto D., Minns D., et al. Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells. Gut. 2020;69:578–590. doi: 10.1136/gutjnl-2019-318483. PubMed DOI PMC

Chiang H.Y., Lu H.-H., Sudhakar J.N., Chen Y.-W., Shih N.-S., Weng Y.-T., Shui J.-W. IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence. Nat. Commun. 2022;13:874. doi: 10.1038/s41467-022-28478-3. PubMed DOI PMC

Hira K., Sajeli Begum A. Methods for Evaluation of TNF-α Inhibition Effect. Methods Mol. Biol. 2021;2248:271–279. PubMed

Sethi J.K., Hotamisligil G.S. Metabolic Messengers: Tumour necrosis factor. Nat. Metab. 2021;3:1302–1312. doi: 10.1038/s42255-021-00470-z. PubMed DOI

Ghoreschi K., Laurence A., Yang X.-P., Tato C.M., McGeachy M.J., Konkel J.E., Ramos H.L., Wei L., Davidson T.S., Bouladoux N., et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature. 2010;467:967–971. doi: 10.1038/nature09447. PubMed DOI PMC

Brenner D., Blaser H., Mak T.W. Regulation of tumour necrosis factor signalling: Live or let die. Nat. Rev. Immunol. 2015;15:362–374. doi: 10.1038/nri3834. PubMed DOI

Sabio G., Davis R.J. TNF and MAP kinase signalling pathways. Semin. Immunol. 2014;26:237–245. doi: 10.1016/j.smim.2014.02.009. PubMed DOI PMC

Bradley J.R. TNF-mediated inflammatory disease. J. Pathol. 2008;214:149–160. doi: 10.1002/path.2287. PubMed DOI

Alam M.S., Otsuka S., Wong N., Abbasi A., Gaida M.M., Fan Y., Meerzaman D., Ashwell J.D. TNF plays a crucial role in inflammation by signaling via T cell TNFR2. Proc. Natl. Acad. Sci. USA. 2021;118:e2109972118. doi: 10.1073/pnas.2109972118. PubMed DOI PMC

Harbour S.N., Maynard C.L., Zindl C.L., Schoeb T.R., Weaver C.T. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc. Natl. Acad. Sci. USA. 2015;112:7061–7066. doi: 10.1073/pnas.1415675112. PubMed DOI PMC

Wertz I.E. TNFR1-activated NF-κB signal transduction: Regulation by the ubiquitin/proteasome system. Curr. Opin. Chem. Biol. 2014;23:71–77. doi: 10.1016/j.cbpa.2014.10.011. PubMed DOI

Van Quickelberghe E., De Sutter D., van Loo G., Eyckerman S., Gevaert K. A protein-protein interaction map of the TNF-induced NF-κB signal transduction pathway. Sci. Data. 2018;5:180289. doi: 10.1038/sdata.2018.289. PubMed DOI PMC

Jang D.I., Lee A.-H., Shin H.-Y., Song H.-R., Park J.-H., Kang T.-B., Lee S.-R., Yang S.-H. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int. J. Mol. Sci. 2021;22:2719. doi: 10.3390/ijms22052719. PubMed DOI PMC

Sedger L.M., McDermott M.F. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants—Past, present and future. Cytokine Growth Factor Rev. 2014;25:453–472. doi: 10.1016/j.cytogfr.2014.07.016. PubMed DOI

Liu S.Q., Ren C., Yao R.-Q., Wu Y., Luan Y.-Y., Dong N., Yao Y.-M. TNF-α-induced protein 8-like 2 negatively regulates the immune function of dendritic cells by suppressing autophagy via the TAK1/JNK pathway in septic mice. Cell Death Dis. 2021;12:1032. doi: 10.1038/s41419-021-04327-x. PubMed DOI PMC

Zou Z., Li M., Zhou Y., Li J., Pan T., Lai L., Wang Q., Zhang L., Wang Q., Song Y., et al. Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Negatively Regulates Innate Immunity Against RNA Virus by Targeting RIG-I in Macrophages. Front. Immunol. 2021;12:642715. doi: 10.3389/fimmu.2021.642715. PubMed DOI PMC

Luan Y.Y., Yao Y.-M., Zhang L., Dong N., Zhang Q.-H., Yu Y., Sheng Z.-Y. Expression of tumor necrosis factor-α induced protein 8 like-2 contributes to the immunosuppressive property of CD4+CD25+ regulatory T cells in mice. Mol. Immunol. 2011;49:219–226. doi: 10.1016/j.molimm.2011.08.016. PubMed DOI

Sun H., Gong S., Carmody R.J., Hilliard A., Li L., Sun J., Kong L., Xu L., Hilliard B., Hu S., et al. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 2008;133:415–426. doi: 10.1016/j.cell.2008.03.026. PubMed DOI PMC

Kumar D., Gokhale P., Broustas C., Chakravarty D., Ahmad I., Kasid U. Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene. 2004;23:612–616. doi: 10.1038/sj.onc.1207123. PubMed DOI

Oho M., Nakano R., Nakayama R., Sakurai W., Miyamoto A., Masuhiro Y., Hanazawa S. TIPE2 (Tumor Necrosis Factor α-induced Protein 8-like 2) Is a Novel Negative Regulator of TAK1 Signal. J. Biol. Chem. 2016;291:22650. doi: 10.1074/jbc.M116.733451. PubMed DOI PMC

Xu Y.R., Lei C.Q. TAK1-TABs Complex: A Central Signalosome in Inflammatory Responses. Front. Immunol. 2021;11:608976. doi: 10.3389/fimmu.2020.608976. PubMed DOI PMC

Liu R., Liu C., Liu C., Fan T., Geng W., Ruan Q. TIPE2 in dendritic cells inhibits the induction of pTregs in the gut mucosa. Biochem. Biophys. Res. Commun. 2019;509:911–917. doi: 10.1016/j.bbrc.2019.01.008. PubMed DOI

Siakavellas S.I., Bamias G. Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation. Inflamm. Bowel Dis. 2015;21:2441–2452. doi: 10.1097/MIB.0000000000000492. PubMed DOI

Tougaard P., Zervides K.A., Skov S., Hansen A.K., Pedersen A.E. Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders. Immunopharmacol. Immunotoxicol. 2016;38:29–38. doi: 10.3109/08923973.2015.1130721. PubMed DOI

Gubatan J., Keyashian K., Rubin S.J., Wang J., Buckman C., Sinha S. Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. Clin. Exp. Gastroenterol. 2021;14:333. doi: 10.2147/CEG.S293272. PubMed DOI PMC

Pang X., He X., Qiu Z., Zhang H., Xie R., Liu Z., Gu Y., Zhao N., Xiang Q., Cui Y. Targeting integrin pathways: Mechanisms and advances in therapy. Signal Transduct. Target. Ther. 2023;8:1. doi: 10.1038/s41392-022-01259-6. PubMed DOI PMC

Ferreira E.F.B., Silva L.B., Cruz J.V., Araújo P.H.F., Kimani N.M., Leite F.H.A., Campos J.M., Santos C.B.R. An Overview of the α4β1 Integrin and the Potential Therapeutic Role of its Antagonists. Curr. Med. Chem. 2021;28:5884–5895. doi: 10.2174/0929867328666210217153609. PubMed DOI

Wight T.N., Potter-Perigo S. The extracellular matrix: An active or passive player in fibrosis? Am. J. Physiol. Gastrointest. Liver Physiol. 2011;301:G950–G955. doi: 10.1152/ajpgi.00132.2011. PubMed DOI PMC

Johnson L.A., Rodansky E.S., Sauder K.L., Horowitz J.C., Mih J.D., Tschumperlin D.J., Higgins P.D. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm. Bowel Dis. 2013;19:891–903. doi: 10.1097/MIB.0b013e3182813297. PubMed DOI PMC

Slack R.J., Macdonald S.J.F., Roper J.A., Jenkins R.G., Hatley R.J.D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov. 2022;21:60–78. doi: 10.1038/s41573-021-00284-4. PubMed DOI PMC

Kotsiliti E. Integrin-based therapy in IBD. Nat. Rev. Gastroenterol. Hepatol. 2021;18:747. doi: 10.1038/s41575-021-00526-1. PubMed DOI

Ferretti F., Cannatelli R., Monico M.C., Maconi G., Ardizzone S. An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis. J. Clin. Med. 2022;11:2302. doi: 10.3390/jcm11092302. PubMed DOI PMC

Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium—PMC. [(accessed on 21 November 2023)]; Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445254/

Plevris N., Chuah C.S., Allen R.M., Arnott I.D., Brennan P.N., Chaudhary S., Churchhouse A.M.D., Din S., Donoghue E., Gaya D.R., et al. Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort. J. Crohn’s Colitis. 2019;13:1111–1120. doi: 10.1093/ecco-jcc/jjz042. PubMed DOI

Gordon F.H., Lai C.W., Hamilton M.I., Allison M.C., Srivastava E.D., Fouweather M.G., Donoghue S., Greenlees C., Subhani J., Amlot P.L., et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to α4 integrin in active Crohn’s disease. Gastroenterology. 2001;121:268–274. doi: 10.1053/gast.2001.26260. PubMed DOI

Amiot A., Serrero M., Peyrin-Biroulet L., Filippi J., Pariente B., Roblin X., Buisson A., Stefanescu C., Trang-Poisson C., Altwegg R., et al. One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: A prospective multicentre cohort study. Aliment. Pharmacol. Ther. 2017;46:310–321. doi: 10.1111/apt.14167. PubMed DOI

Ko H.H., Bressler B. Natalizumab: Pharmacology, clinical efficacy and safety in the treatment of patients with Crohn’s disease. Expert Rev. Gastroenterol. Hepatol. 2007;1:29–39. doi: 10.1586/17474124.1.1.29. PubMed DOI

Vermeire S., O’Byrne S., Keir M., Williams M., Lu T.T., Mansfield J.C., Lamb C.A., Feagan B.G., Panes J., Salas A., et al. Etrolizumab as induction therapy for ulcerative colitis: A randomised, controlled, phase 2 trial. Lancet. 2014;384:309–318. doi: 10.1016/S0140-6736(14)60661-9. PubMed DOI

Feagan B.G., Rutgeerts P., Sands B.E., Hanauer S., Colombel J.-F., Sandborn W.J., Van Assche G., Axler J., Kim H.-J., Danese S., et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2013;369:699–710. doi: 10.1056/NEJMoa1215734. PubMed DOI

Targan S.R., Feagan B.G., Fedorak R.N., Lashner B.A., Panaccione R., Present D.H., Spehlmann M.E., Rutgeerts P.J., Tulassay Z., Volfova M., et al. Natalizumab for the treatment of active Crohn’s disease: Results of the ENCORE Trial. Gastroenterology. 2007;132:1672–1683. doi: 10.1053/j.gastro.2007.03.024. PubMed DOI

Sandborn W.J., Colombel J.F., Enns R., Feagan B.G., Hanauer S.B., Lawrance I.C., Panaccione R., Sanders M., Schreiber S., Targan S., et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N. Engl. J. Med. 2005;353:1912–1925. doi: 10.1056/NEJMoa043335. PubMed DOI

Ghosh S., Goldin E., Gordon F.H., Malchow H.A., Rask-Madsen J., Rutgeerts P., Vyhnálek P., Zádorová Z., Palmer T., Donoghue S. Natalizumab for active Crohn’s disease. N. Engl. J. Med. 2003;348:24–32. doi: 10.1056/NEJMoa020732. PubMed DOI

Rutgeerts P.J., Fedorak R.N., Hommes D.W., Sturm A., Baumgart D.C., Bressler B., Schreiber S., Mansfield J.C., Williams M., Tang M., et al. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis. Gut. 2013;62:1122–1130. doi: 10.1136/gutjnl-2011-301769. PubMed DOI PMC

Tew G.W., Hackney J.A., Gibbons D., Lamb C.A., Luca D., Egen J.G., Diehl L., Anderson J.E., Vermeire S., Mansfield J.C., et al. Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis. Gastroenterology. 2016;150:477–487.e9. doi: 10.1053/j.gastro.2015.10.041. PubMed DOI

A Study of the Efficacy and Safety of Etrolizumab Treatment in Maintenance of Disease Remission in Ulcerative Colitis (UC) Participants Who Are Naive to Tumor Necrosis Factor (TNF) Inhibitors—Full Text View—ClinicalTrials.gov. [(accessed on 21 November 2023)]; Available online: https://classic.clinicaltrials.gov/ct2/show/NCT02165215.

Sandborn W.J., Vermeire S., Tyrrell H., Hassanali A., Lacey S., Tole S., Tatro A.R., The Etrolizumab Global Steering Committee Etrolizumab for the Treatment of Ulcerative Colitis and Crohn’s Disease: An Overview of the Phase 3 Clinical Program. Adv. Ther. 2020;37:3417–3431. doi: 10.1007/s12325-020-01366-2. PubMed DOI PMC

Peyrin-Biroulet L., Hart A., Bossuyt P., Long M., Allez M., Juillerat P., Armuzzi A., Loftus E.V., Ostad-Saffari E., Scalori A., et al. Etrolizumab as ind+uction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): A phase 3, randomised, controlled trial. Lancet Gastroenterol. Hepatol. 2022;7:128–140. doi: 10.1016/S2468-1253(21)00298-3. PubMed DOI

Sandborn W.J., Panés J., Danese S., Sharafali Z., Hassanali A., Jacob-Moffatt R., Eden C., Daperno M., Valentine J.F., Laharie D., et al. Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease (BERGAMOT): A randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 2023;8:43–55. doi: 10.1016/S2468-1253(22)00303-X. PubMed DOI

McLean L.P., Cross R.K. Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease. Expert Opin. Investig. Drugs. 2016;25:263–273. doi: 10.1517/13543784.2016.1148137. PubMed DOI PMC

Solitano V., Parigi T.L., Ragaini E., Danese S. Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): Insights into promising agents. Expert Opin. Investig. Drugs. 2021;30:1037–1046. doi: 10.1080/13543784.2021.1974396. PubMed DOI

Mattheakis L., Fosser C., Saralaya R., Horsch K., Rao N., Bai L., Zhao L., Annamalai T., Liu D. P113 Model based predictions of the PTG-100 pharmacodynamic responses in ulcerative colitis patients. J. Crohn’s Colitis. 2017;11:S132–S133. doi: 10.1093/ecco-jcc/jjx002.239. DOI

Sandborn W.J., Lee S.D., Tarabar D., Louis E., Klopocka M., Klaus J., Reinisch W., Hébuterne X., Park D.-I., Schreiber S., et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn’s disease: Report of the OPERA study. Gut. 2018;67:1824–1835. doi: 10.1136/gutjnl-2016-313457. PubMed DOI PMC

Vermeire S., Sandborn W.J., Danese S., Hébuterne X., Salzberg B.A., Klopocka M., Tarabar D., Vanasek T., Greguš M., Hellstern P.A., et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:135–144. doi: 10.1016/S0140-6736(17)30930-3. PubMed DOI

Nigam G.B., Limdi J.K. An update on the role of anti-IL-12/IL23 agents in the management of inflammatory bowel disease. Br. Med. Bull. 2021;138:29–40. doi: 10.1093/bmb/ldab001. PubMed DOI

McDonald B.D., Dyer E.C., Rubin D.T. IL-23 Monoclonal Antibodies for IBD: So Many, So Different? J. Crohn’s Colitis. 2022;16:II42–II53. doi: 10.1093/ecco-jcc/jjac038. PubMed DOI PMC

Almradi A., Hanzel J., Sedano R., Parker C.E., Feagan B.G., Ma C., Jairath V. Clinical Trials of IL-12/IL-23 Inhibitors in Inflammatory Bowel Disease. BioDrugs. 2020;34:713–721. doi: 10.1007/s40259-020-00451-w. PubMed DOI

Sandborn W.J., Gasink C., Gao L.-L., Blank M.A., Johanns J., Guzzo C., Sands B.E., Hanauer S.B., Targan S., Rutgeerts P., et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N. Engl. J. Med. 2012;367:1519–1528. doi: 10.1056/NEJMoa1203572. PubMed DOI

Iborra M., Beltrán B., Fernández-Clotet A., Gutiérrez A., Antolín B., Huguet J., De Francisco R., Merino O., Carpio D., García-López S., et al. Real-world short-term effectiveness of ustekinumab in 305 patients with Crohn’s disease: Results from the ENEIDA registry. Aliment. Pharmacol. Ther. 2019;50:278–288. doi: 10.1111/apt.15371. PubMed DOI

D’amico F., Peyrin-Biroulet L., Danese S. Ustekinumab in Crohn’s Disease: New Data for Positioning in Treatment Algorithm. J. Crohn’s Colitis. 2022;16:II30–II41. doi: 10.1093/ecco-jcc/jjac011. PubMed DOI PMC

Honap S., Meade S., Ibraheim H., Irving P.M., Jones M.P., Samaan M.A. Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Dig. Dis. Sci. 2022;67:1018–1035. doi: 10.1007/s10620-021-06932-4. PubMed DOI

Davies S.C., Nguyen T.M., Parker C.E., MacDonald J.K., Khanna R., Cochrane IBD Group Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn’s disease. Cochrane Database Syst. Rev. 2019;2019:CD012804. doi: 10.1002/14651858.CD012804.pub2. PubMed DOI PMC

Zhou H., Wang F., Wan J., Su S., Shi Y., Li X., Wu T., Liang J. Systematic Review and Meta-Analysis of Observational Studies on the Effectiveness and Safety of Ustekinumab among Patients with Inflammatory Bowel Disease in Eastern and Western Countries. J. Clin. Med. 2023;12:1894. doi: 10.3390/jcm12051894. PubMed DOI PMC

Yao J.Y., Zhang M., Wang W., Peng X., Zhao J.-Z., Liu T., Li Z.-W., Sun H.-T., Hu P., Zhi M. Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn’s disease: A Chinese real-world study. BMC Gastroenterol. 2021;21:380. doi: 10.1186/s12876-021-01946-8. PubMed DOI PMC

Hirayama H., Morita Y., Imai T., Takahashi K., Yoshida A., Bamba S., Inatomi O., Andoh A. Ustekinumab trough levels predicting laboratory and endoscopic remission in patients with Crohn’s disease. BMC Gastroenterol. 2022;22:195. doi: 10.1186/s12876-022-02271-4. PubMed DOI PMC

Eberl A., Hallinen T., Björkesten C.-G.A., Heikkinen M., Hirsi E., Kellokumpu M., Koskinen I., Moilanen V., Nielsen C., Nuutinen H., et al. Ustekinumab for Crohn’s disease: A nationwide real-life cohort study from Finland (FINUSTE) Scand. J. Gastroenterol. 2019;54:718–725. doi: 10.1080/00365521.2019.1624817. PubMed DOI

Torres J., Bonovas S., Doherty G., Kucharzik T., Gisbert J.P., Raine T., Adamina M., Armuzzi A., Bachmann O., Bager P., et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J. Crohn’s Colitis. 2020;14:4–22. doi: 10.1093/ecco-jcc/jjz180. PubMed DOI

Chiappetta M.F., Viola A., Mastronardi M., Turchini L., Carparelli S., Orlando A., Biscaglia G., Miranda A., Guida L., Costantino G., et al. One-year effectiveness and safety of ustekinumab in ulcerative colitis: A multicenter real-world study from Italy. Expert Opin. Biol. Ther. 2021;21:1483–1489. doi: 10.1080/14712598.2021.1981855. PubMed DOI

Gisbert J.P., Parody-Rúa E., Chaparro M. Efficacy, Effectiveness, and Safety of Ustekinumab for the Treatment of Ulcerative Colitis: A Systematic Review. Inflamm. Bowel Dis. 2023:izac275. doi: 10.1093/ibd/izac275. PubMed DOI PMC

Bar-Gil Shitrit A., Ben-Ya’acov A., Siterman M., Waterman M., Hirsh A., Schwartz D., Zittan E., Adler Y., Koslowsky B., Avni-Biron I., et al. Safety and effectiveness of ustekinumab for induction of remission in patients with Crohn’s disease: A multicenter Israeli study. United Eur. Gastroenterol. J. 2020;8:418. doi: 10.1177/2050640620902956. PubMed DOI PMC

Danese S., Sands B.E., Abreu M.T., O’brien C.D., Bravatà I., Nazar M., Miao Y., Wang Y., Rowbotham D., Leong R.W., et al. Early Symptomatic Improvement After Ustekinumab Therapy in Patients With Ulcerative Colitis: 16-Week Data From the UNIFI Trial. Clin. Gastroenterol. Hepatol. 2022;20:2858–2867.e5. doi: 10.1016/j.cgh.2022.02.050. PubMed DOI

Vieujean S., Louis E., Danese S., Peyrin-Biroulet L. A critical review of ustekinumab for the treatment of active ulcerative colitis in adults. Expert Rev. Gastroenterol. Hepatol. 2023;17:413–430. doi: 10.1080/17474124.2023.2194632. PubMed DOI

Pauwels R.W.M., Huinink S.T.B., van der Woude C.J., Doukas M., Oudijk L., de Vries A.C. Early fecal calprotectin levels at week 8 may guide therapeutic decisions on Ustekinumab therapy in patients with Crohn’s disease. Scand. J. Gastroenterol. 2023;58:980–987. doi: 10.1080/00365521.2023.2194009. PubMed DOI

Rosh J.R., Turner D., Griffiths A., Cohen S.A., Jacobstein D., Adedokun O.J., Padgett L., Terry N.A., O’Brien C., Hyams J.S. Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn’s Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study. J. Crohn’s Colitis. 2021;15:1931–1942. doi: 10.1093/ecco-jcc/jjab089. PubMed DOI PMC

Takeuchi I., Arai K., Kyodo R., Sato T., Tokita K., Hirano Y., Shimizu H. Ustekinumab for children and adolescents with inflammatory bowel disease at a tertiary children’s hospital in Japan. J. Gastroenterol. Hepatol. 2021;36:125–130. doi: 10.1111/jgh.15128. PubMed DOI

Panaccione R., Sandborn W.J., Gordon G.L., Lee S.D., Safdi A., Sedghi S., Feagan B.G., Hanauer S., Reinisch W., Valentine J.F., et al. Briakinumab for Treatment of Crohn’s Disease: Results of a Randomized Trial. Inflamm. Bowel Dis. 2015;21:1329. PubMed PMC

Chavannes M., Martinez-Vinson C., Hart L., Kaniki N., Chao C.-Y., Lawrence S., Jacobson K., Hugot J.-P., Viala J., Deslandres C., et al. Management of Paediatric Patients With Medically Refractory Crohn’s Disease Using Ustekinumab: A Multi-Centred Cohort Study. J. Crohn’s Colitis. 2019;13:578–584. doi: 10.1093/ecco-jcc/jjy206. PubMed DOI

Sandborn W.J., D’haens G.R., Reinisch W., Panés J., Chan D., Gonzalez S., Weisel K., Germinaro M., Frustaci M.E., Yang Z., et al. Guselkumab for the Treatment of Crohn’s Disease: Induction Results From the Phase 2 GALAXI-1 Study. Gastroenterology. 2022;162:1650–1664.e8. doi: 10.1053/j.gastro.2022.01.047. PubMed DOI

Sands B.E., Chen J., Feagan B.G., Penney M., Rees W.A., Danese S., Higgins P.D.R., Newbold P., Faggioni R., Patra K., et al. Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn’s Disease: A Phase 2a Study. Gastroenterology. 2017;153:77–86.e6. doi: 10.1053/j.gastro.2017.03.049. PubMed DOI

Feagan B.G., Sandborn W.J., D’Haens G., Panés J., Kaser A., Ferrante M., Louis E., Franchimont D., Dewit O., Seidler U., et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: A randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389:1699–1709. PubMed

Sandborn W.J., Ferrante M., Bhandari B.R., Berliba E., Feagan B.G., Hibi T., Tuttle J.L., Klekotka P., Friedrich S., Durante M., et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis. Gastroenterology. 2020;158:537–549.e10. doi: 10.1053/j.gastro.2019.08.043. PubMed DOI

Hanžel J., D’Haens G.R. Anti-interleukin-23 agents for the treatment of ulcerative colitis. Expert Opin. Biol. Ther. 2020;20:399–406. doi: 10.1080/14712598.2020.1697227. PubMed DOI

D’Haens G., Panaccione R., Baert F., Bossuyt P., Colombel J.-F., Danese S., Dubinsky M., Feagan B.G., Hisamatsu T., Lim A., et al. Risankizumab as induction therapy for Crohn’s disease: Results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399:2015–2030. doi: 10.1016/S0140-6736(22)00467-6. PubMed DOI

Ferrante M., Panaccione R., Baert F., Bossuyt P., Colombel J.-F., Danese S., Dubinsky M., Feagan B.G., Hisamatsu T., Lim A., et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: Results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022;399:2031–2046. doi: 10.1016/S0140-6736(22)00466-4. PubMed DOI

Kashani A., Schwartz D.A. The Expanding Role of Anti–IL-12 and/or Anti–IL-23 Antibodies in the Treatment of Inflammatory Bowel Disease. Gastroenterol. Hepatol. 2019;15:255. PubMed PMC

Atreya R., Neurath M.F. IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality. J. Crohn’s Colitis. 2022;16:II54–II63. doi: 10.1093/ecco-jcc/jjac007. PubMed DOI PMC

Wang J., Macoritto M., Guay H., Davis J.W., Levesque M.C., Cao X. The Clinical Response of Upadacitinib and Risankizumab Is Associated With Reduced Inflammatory Bowel Disease Anti-TNF-α Inadequate Response Mechanisms. Inflamm. Bowel Dis. 2023;29:771–782. doi: 10.1093/ibd/izac246. PubMed DOI

Schmitt H., Billmeier U., Dieterich W., Rath T., Sonnewald S., Reid S., Hirschmann S., Hildner K., Waldner M.J., Mudter J., et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut. 2019;68:814–828. doi: 10.1136/gutjnl-2017-315671. PubMed DOI PMC

Marsal J., Acosta M.B.-D., Blumenstein I., Cappello M., Bazin T., Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front. Med. 2022;9:897936. doi: 10.3389/fmed.2022.897936. PubMed DOI PMC

Evangelatos G., Bamias G., Kitas G.D., Kollias G., Sfikakis P.P. The second decade of anti-TNF-a therapy in clinical practice: New lessons and future directions in the COVID-19 era. Rheumatol. Int. 2022;42:1493. doi: 10.1007/s00296-022-05136-x. PubMed DOI PMC

Juillerat P., Grueber M.M., Ruetsch R., Santi G., Vuillèmoz M., Michetti P. Positioning biologics in the treatment of IBD: A practical guide—Which mechanism of action for whom? Curr. Res. Pharmacol. Drug Discov. 2022;3:100104. doi: 10.1016/j.crphar.2022.100104. PubMed DOI PMC

Papamichael K., Rivals-Lerebours O., Billiet T., Casteele N.V., Gils A., Ferrante M., Van Assche G., Rutgeerts P.J., Mantzaris G.J., Peyrin-Biroulet L., et al. Long-Term Outcome of Patients with Ulcerative Colitis and Primary Non-response to Infliximab. J. Crohn’s Colitis. 2016;10:1015–1023. doi: 10.1093/ecco-jcc/jjw067. PubMed DOI

Kassouri L., Amiot A., Kirchgesner J., Tréton X., Allez M., Bouhnik Y., Beaugerie L., Carbonnel F., Meyer A. The outcome of Crohn’s disease patients refractory to anti-TNF and either vedolizumab or ustekinumab. Dig. Liver Dis. 2020;52:1148–1155. doi: 10.1016/j.dld.2020.07.031. PubMed DOI

Etiology and Management of Lack or Loss of Response to Anti-Tumor Necrosis Factor Therapy in Patients with Inflammatory Bowel Disease—PubMed. [(accessed on 21 November 2023)]; Available online: https://pubmed.ncbi.nlm.nih.gov/31892912/ PubMed PMC

Kennedy N.A., Heap G.A., Green H.D., Hamilton B., Bewshea C., Walker G.J., Thomas A., Nice R., Perry M.H., Bouri S., et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: A prospective, multicentre, cohort study. Lancet Gastroenterol. Hepatol. 2019;4:341–353. doi: 10.1016/S2468-1253(19)30012-3. PubMed DOI

Solitano V., Facciorusso A., McGovern D.P., Nguyen T., Colman R.J., Zou L., Boland B.S., Syversen S.W., Jørgensen K.K., Ma C., et al. HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol. 2023;21:3019–3029.e5. doi: 10.1016/j.cgh.2023.03.044. PubMed DOI

Fuentes-Valenzuela E., García-Alonso F.J., Maroto-Martín C., Casamayor L.J., Garrote J.A., Muñoz R.A., De Prado Á., Castrodeza A.V., Marinero M., Carbajosa R.C., et al. Influence of HLADQA1*05 Genotype in Adults With Inflammatory Bowel Disease and Anti-TNF Treatment With Proactive Therapeutic Drug Monitoring: A Retrospective Cohort Study. Inflamm, Bowel Dis. 2023;29:izac259. doi: 10.1093/ibd/izac259. PubMed DOI

Sazonovs A., Kennedy N.A., Moutsianas L., Heap G.A., Rice D.L., Reppell M., Bewshea C.M., Chanchlani N., Walker G.J., Perry M.H., et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology. 2020;158:189–199. doi: 10.1053/j.gastro.2019.09.041. PubMed DOI

Wilson A., Peel C., Wang Q., Pananos A.D., Kim R.B. HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease. Aliment. Pharmacol. Ther. 2020;51:356–363. doi: 10.1111/apt.15563. PubMed DOI

Sazonovs A., Ahmad T., Anderson C.A. Underpowered PANTS: A Response to the Conclusions of ‘Extended Analysis Identifies Drug-Specific Association of Two Distinct HLA Class II Haplotypes for Development of Immunogenicity to Adalimumab and Infliximab’. Gastroenterology. 2021;160:470–471. doi: 10.1053/j.gastro.2020.05.102. PubMed DOI

Lamb C.A., Kennedy N.A., Raine T., Hendy P.A., Smith P.J., Limdi J.K., Hayee B., Lomer M.C.E., Parkes G.C., Selinger C., et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68:s1–s106. doi: 10.1136/gutjnl-2019-318484. PubMed DOI PMC

West N.R., Hegazy A.N., Owens B.M.J., Bullers S.J., Linggi B., Buonocore S., Coccia M., Görtz D., This S., Stockenhuber K., et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 2017;23:579–589. doi: 10.1038/nm.4307. PubMed DOI PMC

Guo A., Ross C., Chande N., Gregor J., Ponich T., Khanna R., Sey M., Beaton M., Yan B., Kim R.B., et al. High oncostatin M predicts lack of clinical remission for patients with inflammatory bowel disease on tumor necrosis factor α antagonists. Sci. Rep. 2022;12:1185. doi: 10.1038/s41598-022-05208-9. PubMed DOI PMC

Aguilar D., Revilla L., Garrido-Trigo A., Panés J., Lozano J.J., Planell N., Esteller M., Lacerda A.P., Guay H., Butler J., et al. Randomized Controlled Trial Substudy of Cell-specific Mechanisms of Janus Kinase 1 Inhibition With Upadacitinib in the Crohn’s Disease Intestinal Mucosa: Analysis From the CELEST Study. Inflamm. Bowel Dis. 2021;27:1999–2009. doi: 10.1093/ibd/izab116. PubMed DOI PMC

Sandborn W.J., Ghosh S., Panes J., Vranic I., Wang W., Niezychowski W., Study A3921043 Investigators A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 2014;12:1485–1493. doi: 10.1016/j.cgh.2014.01.029. PubMed DOI

Sands B.E., Sandborn W.J., Van Assche G., Lukas M., Xu J., James A., Abhyankar B., Lasch K. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm. Bowel Dis. 2017;23:97–106. doi: 10.1097/MIB.0000000000000979. PubMed DOI

Singh S., George J., Boland B.S., Vande Casteele N., Sandborn W.J. Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. J. Crohn’s Colitis. 2018;12:635–643. doi: 10.1093/ecco-jcc/jjy004. PubMed DOI PMC

Matsuoka K., Hibi T. Etrasimod for ulcerative colitis: Evaluating phase III results. Nat. Rev. Gastroenterol. Hepatol. 2023;20:762–763. doi: 10.1038/s41575-023-00793-0. PubMed DOI

Sandborn W.J., Vermeire S., Peyrin-Biroulet L., Dubinsky M.C., Panes J., Yarur A., Ritter T., Baert F., Schreiber S., Sloan S., et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): Two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401:1159–1171. doi: 10.1016/S0140-6736(23)00061-2. PubMed DOI

Grossberg L.B., Papamichael K., Cheifetz A.S. Review article: Emerging drug therapies in inflammatory bowel disease. Aliment. Pharmacol. Ther. 2022;55:789–804. doi: 10.1111/apt.16785. PubMed DOI

Zhou L., Todorovic V. Interleukin-36: Structure, Signaling and Function. Adv. Exp. Med. Biol. 2021;21:191–210. PubMed

Blair H.A. Spesolimab: First Approval. Drugs. 2022;82:1681–1686. doi: 10.1007/s40265-022-01801-4. PubMed DOI PMC

Ferrante M., Irving P.M., Selinger C.P., D’haens G., Kuehbacher T., Seidler U., Gropper S., Haeufel T., Forgia S., Danese S., et al. Safety and tolerability of spesolimab in patients with ulcerative colitis. Expert Opin. Drug Saf. 2023;22:141–152. doi: 10.1080/14740338.2022.2103536. PubMed DOI

Melton E., Qiu H. Interleukin-36 Cytokine/Receptor Signaling: A New Target for Tissue Fibrosis. Int. J. Mol. Sci. 2020;21:6458. doi: 10.3390/ijms21186458. PubMed DOI PMC

Zhang M., Perrin L., Pardo P. A Randomized Phase 1 Study to Assess the Safety and Pharmacokinetics of the Subcutaneously Injected Anti-LIGHT Antibody, SAR252067. Clin. Pharmacol. Drug Dev. 2017;6:292–301. doi: 10.1002/cpdd.295. PubMed DOI

Shi F., Xiong Y., Zhang Y., Qiu C., Li M., Shan A., Yang Y., Li B. The Role of TNF Family Molecules Light in Cellular Interaction Between Airway Smooth Muscle Cells and T Cells During Chronic Allergic Inflammation. Inflammation. 2018;41:1021–1031. doi: 10.1007/s10753-018-0755-1. PubMed DOI

Santacroce G., Lenti M.V., Di Sabatino A. Therapeutic Targeting of Intestinal Fibrosis in Crohn’s Disease. Cells. 2022;11:429. doi: 10.3390/cells11030429. PubMed DOI PMC

Fischer R., Kontermann R.E., Pfizenmaier K. Selective Targeting of TNF Receptors as a Novel Therapeutic Approach. Front. Cell Dev. Biol. 2020;8:401. doi: 10.3389/fcell.2020.00401. PubMed DOI PMC

Pegoretti V., Bauer J., Fischer R., Paro I., Douwenga W., Kontermann R.E., Pfizenmaier K., Houben E., Broux B., Hellings N., et al. Sequential treatment with a TNFR2 agonist and a TNFR1 antagonist improves outcomes in a humanized mouse model for MS. J. Neuroinflamm. 2023;20:106. doi: 10.1186/s12974-023-02785-y. PubMed DOI PMC

Marchetti L., Klein M., Schlett K., Pfizenmaier K., Eisel U.L.M. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J. Biol. Chem. 2004;279:32869–32881. doi: 10.1074/jbc.M311766200. PubMed DOI

Zhou X., Kong N., Wang J., Fan H., Zou H., Horwitz D., Brand D., Liu Z., Zheng S.G. Cutting Edge: All-Trans Retinoic Acid Sustains the Stability and Function of Natural Regulatory T Cells in an Inflammatory Milieu. J. Immunol. 2010;185:2675. doi: 10.4049/jimmunol.1000598. PubMed DOI PMC

Yang S., Xie C., Chen Y., Wang J., Chen X., Lu Z., June R.R., Zheng S.G. Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis. 2019;10:27. doi: 10.1038/s41419-018-1266-6. PubMed DOI PMC

Liu J., Zhang H., Su Y., Zhang B. Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases. Cell Biosci. 2022;12:68. doi: 10.1186/s13578-022-00810-w. PubMed DOI PMC

Kucka K., Lang I., Zhang T., Siegmund D., Medler J., Wajant H. Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist. Cell Death Dis. 2021;12:360. doi: 10.1038/s41419-021-03633-8. PubMed DOI PMC

Kang S., Tanaka T., Narazaki M., Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity. 2019;50:1007–1023. doi: 10.1016/j.immuni.2019.03.026. PubMed DOI

Garbers C., Heink S., Korn T., Rose-John S. Interleukin-6: Designing specific therapeutics for a complex cytokine. Nat. Rev. Drug Discov. 2018;17:395–412. doi: 10.1038/nrd.2018.45. PubMed DOI

Gu J., Liu G., Xing J., Song H., Wang Z. Fecal bacteria from Crohn’s disease patients more potently activated NOD-like receptors and Toll-like receptors in macrophages, in an IL-4-repressible fashion. Microb. Pathog. 2018;121:40–44. doi: 10.1016/j.micpath.2018.05.009. PubMed DOI

Terabe F., Fujimoto M., Serada S., Shinzaki S., Iijima H., Tsujii M., Hayashi N., Nomura S., Kawahata H., Jang M.H., et al. Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+ T-cell responses in murine colitis. Inflamm. Bowel Dis. 2011;17:491–502. doi: 10.1002/ibd.21384. PubMed DOI

Ito H. Anti-interleukin-6 therapy for Crohn’s disease. Curr. Pharm. Des. 2003;9:295–305. doi: 10.2174/1381612033391900. PubMed DOI

Han J., Liu X., Xu Y., Wang Q., Li L., Du K., Li C., Liu H., Chen Y., Huang J. Characterization of HZ0412a, a novel potent humanized anti-IL-6 receptor antibody that blocks IL-6R binding to gp130. Antib. Ther. 2023;6:119–126. doi: 10.1093/abt/tbad008. PubMed DOI PMC

Dhimolea E. Canakinumab. MAbs. 2010;2:3–13. doi: 10.4161/mabs.2.1.10328. PubMed DOI PMC

Shaul E., Conrad M.A., Dawany N., Patel T., Canavan M.C., Baccarella A., Weinbrom S., Aleynick D., Sullivan K.E., Kelsen J.R. Canakinumab for the treatment of autoinflammatory very early onset- inflammatory bowel disease. Front. Immunol. 2022;13:972114. doi: 10.3389/fimmu.2022.972114. PubMed DOI PMC

England E., Rees D.G., Scott I.C., Carmen S., Chan D.T.Y., Huntington C.E.C., Houslay K.F., Erngren T., Penney M., Majithiya J.B., et al. Tozorakimab (MEDI3506): An anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Sci. Rep. 2023;13:9825. doi: 10.1038/s41598-023-36642-y. PubMed DOI PMC

Țiburcă L., Bembea M., Zaha D.C., Jurca A.D., Vesa C.M., Rațiu I.A., Jurca C.M. The Treatment with Interleukin 17 Inhibitors and Immune-Mediated Inflammatory Diseases. Curr. Issues Mol. Biol. 2022;44:1851–1866. doi: 10.3390/cimb44050127. PubMed DOI PMC

Cao Y., Dai Y., Zhang L., Wang D., Yu Q., Hu W., Wang X., Yu P., Ping Y., Sun T., et al. Serum oncostatin M is a potential biomarker of disease activity and infliximab response in inflammatory bowel disease measured by chemiluminescence immunoassay. Clin. Biochem. 2022;100:35–41. doi: 10.1016/j.clinbiochem.2021.11.011. PubMed DOI

Verstockt S., Verstockt B., Machiels K., Vancamelbeke M., Ferrante M., Cleynen I., De Hertogh G., Vermeire S. Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2021;27:1564–1575. doi: 10.1093/ibd/izab032. PubMed DOI PMC

Li C., Kuemmerle J.F. The fate of myofibroblasts during the development of fibrosis in Crohn’s disease. J. Dig. Dis. 2020;21:326–331. doi: 10.1111/1751-2980.12852. PubMed DOI

Baghdadi M., Umeyama Y., Hama N., Kobayashi T., Han N., Wada H., Seino K.-I. Interleukin-34, a comprehensive review. J. Leukoc. Biol. 2018;104:931–951. doi: 10.1002/JLB.MR1117-457R. PubMed DOI

Chaudhury A., Howe P.H. The tale of transforming growth factor-beta (TGFbeta) signaling: A soigné enigma. IUBMB Life. 2009;61:929–939. doi: 10.1002/iub.239. PubMed DOI PMC

Wang Y., Zhang Y., Lu B., Xi J., Ocansey D.K.W., Mao F., Hao D., Yan Y. hucMSC-Ex Alleviates IBD-Associated Intestinal Fibrosis by Inhibiting ERK Phosphorylation in Intestinal Fibroblasts. Stem Cells Int. 2023;2023:2828981. doi: 10.1155/2023/2828981. PubMed DOI PMC

Xu W.D., Li R., Huang A.F. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front. Immunol. 2022;13:891328. doi: 10.3389/fimmu.2022.891328. PubMed DOI PMC

Jun Y.K., Kwon S.H., Yoon H.T., Park H., Soh H., Lee H.J., Im J.P., Kim J.S., Kim J.W., Koh S.-J. Toll-like receptor 4 regulates intestinal fibrosis via cytokine expression and epithelial-mesenchymal transition. Sci. Rep. 2020;10:19867. doi: 10.1038/s41598-020-76880-y. PubMed DOI PMC

Wang Y., Wang Z., Yang H., Chen S., Zheng D., Liu X., Jiang Q., Chen Y. Metformin Ameliorates Chronic Colitis-Related Intestinal Fibrosis via Inhibiting TGF-β1/Smad3 Signaling. Front. Pharmacol. 2022;13:887497. doi: 10.3389/fphar.2022.887497. PubMed DOI PMC

Butera A., Quaranta M.T., Crippa L., Spinello I., Saulle E., Di Carlo N., Campanile D., Boirivant M., Labbaye C. CD147 Targeting by AC-73 Induces Autophagy and Reduces Intestinal Fibrosis Associated with TNBS Chronic Colitis. J. Crohn’s Colitis. 2022;16:1751. doi: 10.1093/ecco-jcc/jjac084. PubMed DOI PMC

Xie H., Jiao Y., Zhou X., Liao X., Chen J., Chen H., Chen L., Yu S., Deng Q., Sun L., et al. Integrin αvβ6 contributes to the development of intestinal fibrosis via the FAK/AKT signaling pathway. Exp. Cell Res. 2022;411:113003. doi: 10.1016/j.yexcr.2021.113003. PubMed DOI

Imenez Silva P.H., Wagner C.A. Physiological relevance of proton-activated GPCRs. Pflug. Arch. 2022;474:487–504. doi: 10.1007/s00424-022-02671-1. PubMed DOI PMC

Lee H.J. Therapeutic Potential of the Combination of Pentoxifylline and Vitamin-E in Inflammatory Bowel Disease: Inhibition of Intestinal Fibrosis. J. Clin. Med. 2022;11:4713. doi: 10.3390/jcm11164713. PubMed DOI PMC

Liso M., Verna G., Cavalcanti E., De Santis S., Armentano R., Tafaro A., Lippolis A., Campiglia P., Gasbarrini A., Mastronardi M., et al. Interleukin 1β Blockade Reduces Intestinal Inflammation in a Murine Model of Tumor Necrosis Factor–Independent Ulcerative Colitis. Cell. Mol. Gastroenterol. Hepatol. 2022;14:151. doi: 10.1016/j.jcmgh.2022.03.003. PubMed DOI PMC

Di Martino L., Osme A., Kossak-Gupta S., Pizarro T.T., Cominelli F. TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Immune Pathways. Cell. Mol. Gastroenterol. Hepatol. 2019;8:427. doi: 10.1016/j.jcmgh.2019.05.009. PubMed DOI PMC

New Potential Therapeutic Target Identified for Crohn’s Disease—NIDDK. [(accessed on 21 November 2023)]; Available online: https://www.niddk.nih.gov/news/archive/2021/new-potential-therapeutic-target-identified-crohns-disease.

Vermeire S., Hébuterne X., Tilg H., De Hertogh G., Gineste P., Steens J.-M. Induction and Long-term Follow-up With ABX464 for Moderate-to-severe Ulcerative Colitis: Results of Phase IIa Trial. Gastroenterology. 2021;160:2595–2598.e3. doi: 10.1053/j.gastro.2021.02.054. PubMed DOI

Schreiber S., Aden K., Bernardes J.P., Conrad C., Tran F., Höper H., Volk V., Mishra N., Blase J.I., Nikolaus S., et al. Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease. Gastroenterology. 2021;160:2354–2366.e11. doi: 10.1053/j.gastro.2021.02.062. PubMed DOI

Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis.|UCSF Helen Diller Family Comprehensive Cancer Center. [(accessed on 21 November 2023)]. Available online: https://cancer.ucsf.edu/node/326706.