248
Views
0
CrossRef citations to date
0
Altmetric
Review

Cytokines of the interleukin-6 family as emerging targets in inflammatory bowel disease

&
Pages 57-65 | Received 11 Oct 2023, Accepted 12 Jan 2024, Published online: 23 Jan 2024

References

  • Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015 Apr;12(4):205–17. doi: 10.1038/nrgastro.2015.34
  • Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119–124. doi: 10.1038/nature11582
  • GBDIBD C, Sepanlou SG, Ikuta K. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020 Jan;5(1):17–30. doi: 10.1016/S2468-1253(19)30333-4
  • Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017 Dec 23;390(10114):2769–2778. doi: 10.1016/S0140-6736(17)32448-0
  • Wang R, Li Z, Liu S, et al. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023 Mar 28;13(3):e065186. doi: 10.1136/bmjopen-2022-065186
  • Kobayashi T, Siegmund B, Le Berre C, et al. Ulcerative colitis. Nat Rev Dis Primers. 2020 Sep 10;6(1):74. doi: 10.1038/s41572-020-0205-x
  • Roda G, Chien Ng S, Kotze PG, et al. Crohn’s disease. Nat Rev Dis Primers. 2020 Apr 2;6(1):22. doi: 10.1038/s41572-020-0156-2
  • Knowles SR, Graff LA, Wilding H, et al. Quality of life in inflammatory bowel disease: a systematic review and meta-analyses-part I. Inflamm Bowel Dis. 2018 Mar 19;24(4):742–751. doi: 10.1093/ibd/izx100
  • Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014 Apr;11(4):243–55. doi: 10.1038/nrgastro.2013.253
  • Cui G, Fan Q, Li Z, et al. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: current and novel biomarkers. EBioMedicine. 2021 Apr;66:103329.
  • Leonard WJ, Lin JX. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov. 2023 Oct;22(10):827–854. doi: 10.1038/s41573-023-00746-x
  • Giraldez MD, Carneros D, Garbers C, et al. New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol. 2021 Nov;18(11):787–803.
  • Garbers C, Hermanns H, Schaper F, et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012;23(3):85–97. doi: 10.1016/j.cytogfr.2012.04.001
  • Zhou Y, Stevis PE, Cao J, et al. Structural insights into the assembly of gp130 family cytokine signaling complexes. Sci Adv. 2023 Mar 15;9(11):eade4395. doi: 10.1126/sciadv.ade4395
  • Putoczki TL, Dobson RCJ, Griffin MDW. The structure of human interleukin-11 reveals receptor-binding site features and structural differences from interleukin-6. Acta Crystallogr D Biol Crystallogr. 2014;70(9):2277–2285. doi: 10.1107/S1399004714012267
  • Grötzinger J, Kurapkat G, Wollmer A, et al. The family of the IL-6-type cytokines: specificity and promiscuity of the receptor complexes. Proteins. 1997;27(1):96–109. doi: 10.1002/(SICI)1097-0134(199701)27:1<96:AID-PROT10>3.0.CO;2-D
  • Garbers C, Scheller J. Interleukin-6 and interleukin-11: same same but different. Biol Chem. 2013 Jun 5;394(9):1145–1161. doi: 10.1515/hsz-2013-0166
  • Schumertl T, Lokau J, Rose-John S, et al. Function and proteolytic generation of the soluble interleukin-6 receptor in health and disease. Biochim Biophys Acta, Mol Cell Res. 2022 Jan;1869(1):119143.
  • Lokau J, Kespohl B, Kirschke S, et al. The role of proteolysis in interleukin-11 signaling. Biochim Biophys Acta, Mol Cell Res. 2022 Jan;1869(1):119135.
  • Lokau J, Garbers C. Biological functions and therapeutic opportunities of soluble cytokine receptors. Cytokine Growth Factor Rev. 2020 Apr 18;55:94–108. doi: 10.1016/j.cytogfr.2020.04.003
  • Lokau J, Agthe M, Flynn CM, et al. Proteolytic control of Interleukin-11 and Interleukin-6 biology. Biochim Biophys Acta. 2017 Jun 16;1864(11 Pt B):2105–2117. doi: 10.1016/j.bbamcr.2017.06.008
  • Lust J, Donovan K, Kline M, et al. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine. 1992;4(2):96–100. doi: 10.1016/1043-4666(92)90043-Q
  • Garbers C, Jänner N, Chalaris A, et al. Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem. 2011 Apr 29;286(17):14804–14811. doi: 10.1074/jbc.M111.229393
  • Riethmueller S, Somasundaram P, Ehlers JC, et al. Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-Glycosylation. PLoS Biol. 2017;15(1):e2000080. doi: 10.1371/journal.pbio.2000080
  • Rose-John S, Jenkins BJ, Garbers C, et al. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol. 2023 Oct;23(10):666–681.
  • Koch L, Kespohl B, Agthe M, et al. Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling. FASEB J. 2021;35(3):e21380. doi: 10.1096/fj.202002087R
  • Lokau J, Nitz R, Agthe M, et al. Proteolytic cleavage governs interleukin-11 trans-signaling. Cell Rep. 2016;14(7):1761–1773. doi: 10.1016/j.celrep.2016.01.053
  • Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994;300(Pt 2):281–290. doi: 10.1042/bj3000281
  • Garbers C, Aparicio-Siegmund S, Rose-John S. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol. 2015;34:75–82. doi: 10.1016/j.coi.2015.02.008
  • Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003 Aug 15;374(Pt 1):1–20. doi: 10.1042/bj20030407
  • Heinrich PC, Behrmann I, Müller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334(Pt 2):297–314. doi: 10.1042/bj3340297
  • Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol. 2005 Jan;100(1):64–72.
  • Li Y, de Haar C, Chen M, et al. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut. 2010 Feb;59(2):227–35.
  • Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009 Feb 3;15(2):91–102. doi: 10.1016/j.ccr.2009.01.002
  • Pickert G, Neufert C, Leppkes M, et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009 Jul 6;206(7):1465–72. doi: 10.1084/jem.20082683
  • Pang L, Huynh J, Alorro MG, et al. STAT3 signalling via the IL-6ST/gp130 cytokine receptor promotes epithelial integrity and intestinal barrier function during DSS-Induced colitis. Biomedicines. 2021 Feb 12;9(2):187. doi: 10.3390/biomedicines9020187
  • Takeda K, Clausen BE, Kaisho T, et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999 Jan;10(1):39–49.
  • Alonzi T, Newton IP, Bryce PJ, et al. Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine. 2004 Apr 21;26(2):45–56. doi: 10.1016/j.cyto.2003.12.002
  • Reindl W, Weiss S, Lehr HA, et al. Essential crosstalk between myeloid and lymphoid cells for development of chronic colitis in myeloid-specific signal transducer and activator of transcription 3-deficient mice. Immunology. 2007 Jan;120(1):19–27.
  • Tebbutt N, Giraud A, Inglese M, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nature Med. 2002;8(10):1089–1097. doi: 10.1038/nm763
  • Srivatsa S, Paul MC, Cardone C, et al. EGFR in tumor-associated myeloid cells promotes development of colorectal cancer in mice and associates with outcomes of patients. Gastroenterology. 2017 Jul;153(1):178–190 e10.
  • Putoczki T, Thiem S, Loving A, et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013;24(2):257–271. doi: 10.1016/j.ccr.2013.06.017
  • Nguyen PM, Putoczki TL, Ernst M. STAT3-activating cytokines: a therapeutic opportunity for inflammatory bowel disease? J Interferon Cytokine Res. 2015 May;35(5):340–350. doi: 10.1089/jir.2014.0225
  • Schmidt S, Schumacher N, Schwarz J, et al. ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. J Exp Med. 2018 Apr 2;215(4):1205–1225. doi: 10.1084/jem.20171696
  • Lokau J, Schoeder V, Haybaeck J, et al. Jak-stat signaling induced by interleukin-6 family cytokines in hepatocellular carcinoma. Cancers (Basel). 2019 Nov 1;11(11):1704. doi: 10.3390/cancers11111704
  • Lokau J, Garbers C. Activating mutations of the gp130/JAK/STAT pathway in human diseases. Adv Protein Chem Struct Biol. 2019;116:283–309.
  • Lang VR, Englbrecht M, Rech J, et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology. 2012 May;51(5):852–857.
  • Suzuki Y, Saito H, Kasanuki J, et al. Significant increase of interleukin 6 production in blood mononuclear leukocytes obtained from patients with active inflammatory bowel disease. Life Sci. 1990;47(24):2193–2197. doi: 10.1016/0024-3205(90)90149-L
  • Gross V, Andus T, Caesar I, et al. Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology. 1992 Feb;102(2):514–9.
  • Hyams JS, Fitzgerald JE, Treem WR, et al. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology. 1993 May;104(5):1285–92.
  • Hosokawa T, Kusugami K, Ina K, et al. Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J Gastroenterol Hepatol. 1999 Oct;14(10):987–96.
  • Gustot T, Lemmers A, Louis E, et al. Profile of soluble cytokine receptors in Crohn’s disease. Gut. 2005 Apr;54(4):488–95.
  • Mitsuyama K, Toyonaga A, Sasaki E, et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut. 1995;36(1):45–49. doi: 10.1136/gut.36.1.45
  • Nikolaus S, Waetzig GH, Butzin S, et al. Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases. Int J Colorectal Dis. 2018 Jul;33(7):927–936.
  • Reif A, Lam K, Weidler S, et al. Natural glycoforms of human interleukin 6 show atypical plasma clearance. Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13380–13387. doi: 10.1002/anie.202101496
  • Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut. 2006 Mar;55(3):426–431. doi: 10.1136/gut.2005.069476
  • Garbers C, Monhasery N, Aparicio-Siegmund S, et al. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased Proteolytic conversion rates by ADAM Proteases. Biochim Biophys Acta. 2014;1842(9):1485–1494. doi: 10.1016/j.bbadis.2014.05.018
  • Aparicio-Siegmund S, Garbers Y, Flynn CM, et al. The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2019 Aug 1;317(2):E411–E420. doi: 10.1152/ajpendo.00166.2019
  • Parisinos CA, Serghiou S, Katsoulis M, et al. Variation in interleukin 6 receptor gene associates with risk of crohn’s disease and ulcerative colitis. Gastroenterology. 2018 Aug;155(2):303–306 e2.
  • Yamamoto M, Yoshizaki K, Kishimoto T, et al. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol. 2000 May 1;164(9):4878–82. doi: 10.4049/jimmunol.164.9.4878
  • Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15(2):103–113. doi: 10.1016/j.ccr.2009.01.001
  • Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nature Med. 2000;6(5):583–588. doi: 10.1038/75068
  • Becker C, Fantini M, Schramm C, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004;21(4):491–501. doi: 10.1016/j.immuni.2004.07.020
  • Mitsuyama K, Matsumoto S, Rose-John S, et al. STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut. 2006;55(9):1263–1269. doi: 10.1136/gut.2005.079343
  • Zhang S, Chen B, Wang B, et al. Effect of induction therapy with olamkicept vs placebo on clinical response in patients with active ulcerative colitis: a randomized clinical trial. JAMA. 2023 Mar 7;329(9):725–734. doi: 10.1001/jama.2023.1084
  • Schreiber S, Aden K, Bernardes JP, et al. Therapeutic IL-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease. Gastroenterology. 2021 Mar 2;160(7):2354–2366.e11. doi: 10.1053/j.gastro.2021.02.062
  • Danese S, Vermeire S, Hellstern P, et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut. 2019 Jan;68(1):40–48.
  • 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 Mar;17(1):55–74. doi: 10.1007/s12079-022-00695-x
  • Lokau J, Agthe M, Garbers C. Generation of soluble interleukin-11 and interleukin-6 receptors: a crucial function for proteases during inflammation. Mediators Inflamm. 2016;2016:1785021. doi: 10.1155/2016/1785021
  • Bilinski P, Roopenian D, Gossler A. Maternal IL-11Ralpha function is required for normal decidua and fetoplacental development in mice. Genes Dev. 1998;12(14):2234–2243. doi: 10.1101/gad.12.14.2234
  • Agthe M, Garbers Y, Putoczki T, et al. Interleukin-11 classic but not trans-signaling is essential for fertility in mice. Placenta. 2017;57:13–16. doi: 10.1016/j.placenta.2017.05.015
  • Nieminen P, Morgan N, Fenwick A, et al. Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. Am J Hum Genet. 2011;89(1):67–81. doi: 10.1016/j.ajhg.2011.05.024
  • Kespohl B, Schumertl T, Bertrand J, et al. The cytokine interleukin-11 crucially links bone formation, remodeling and resorption. Cytokine Growth Factor Rev. 2021 Apr 24;60:18–27. doi: 10.1016/j.cytogfr.2021.04.002
  • de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017 Feb;49(2):256–261.
  • Klein W, Tromm A, Griga T, et al. A polymorphism in the IL11 gene is associated with ulcerative colitis. Genes Immun. 2002 Dec;3(8):494–6.
  • Lokau J, Göttert S, Arnold P, et al. The SNP rs4252548 (R112H) which is associated with reduced human height compromises the stability of IL-11. Biochim Biophys Acta. 2018 Dec 10;1865(3):496–506. doi: 10.1016/j.bbamcr.2017.12.003
  • Keith JC Jr., Albert L, Sonis ST, et al. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells. 1994;12 Suppl 1:79–89. discussion 89-90.
  • Qiu BS, Pfeiffer CJ, Keith JC Jr. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci. 1996 Aug;41(8):1625–30. doi: 10.1007/BF02087911
  • Pfeiffer CJ, Sato S, Qiu BS, et al. Cellular pathology of experimental colitis induced by trinitrobenzenesulphonic acid (TNBS): protective effects of recombinant human interleukin-11. Inflammopharmacology. 1997;5(4):363–81. doi: 10.1007/s10787-997-0033-6
  • Peterson R, Wang L, Albert L, et al. Molecular effects of recombinant human interleukin-11 in the HLA-B27 rat model of inflammatory bowel disease. Lab Invest. 1998;78(12):1503–1512. doi: 10.1016/S0016-5085(98)84313-8
  • Meerveld B G-V, Tyler K, JC K Jr. Recombinant human interleukin-11 modulates ion transport and mucosal inflammation in the small intestine and colon. Lab Invest. 2000 Aug;80(8):1269–1280. doi: 10.1038/labinvest.3780135
  • Naugler KM, Baer KA, Ropeleski MJ. Interleukin-11 antagonizes Fas ligand-mediated apoptosis in IEC-18 intestinal epithelial crypt cells: role of MEK and Akt-dependent signaling. Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G728–37. doi: 10.1152/ajpgi.00002.2007
  • Chalaris A, Adam N, Sina C, et al. Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J Exp Med. 2010 Aug 2;207(8):1617–24. doi: 10.1084/jem.20092366
  • Wang H, Wang DH, Yang X, et al. Colitis-induced IL11 promotes colon carcinogenesis. Carcinogenesis. 2021 Apr 30;42(4):557–569. doi: 10.1093/carcin/bgaa122
  • Nishina T, Deguchi Y, Kawauchi M, et al. Interleukin 11 confers resistance to dextran sulfate sodium-induced colitis in mice. iScience. 2023 Feb 17;26(2):105934. doi: 10.1016/j.isci.2023.105934
  • Nishina T, Deguchi Y, Ohshima D, et al. Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer. Nat Commun. 2021 Apr 16;12(1):2281. doi: 10.1038/s41467-021-22450-3
  • Jasso GJ, Jaiswal A, Varma M, et al. Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing. PLoS Biol. 2022 Jan;20(1):e3001532.
  • Gibson D, Montero M, Ropeleski M, et al. Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology. 2010;139(4):1277–1288. doi: 10.1053/j.gastro.2010.06.057
  • Lim WW, Ng B, Widjaja A, et al. Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice. PloS One. 2020;15(1):e0227505. doi: 10.1371/journal.pone.0227505
  • Smillie CS, Biton M, Ordovas-Montanes J, et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell. 2019 Jul 25;178(3):714–730 e22. doi: 10.1016/j.cell.2019.06.029
  • Arijs I, Quintens R, Van Lommel L, et al. Predictive value of epithelial gene expression profiles for response to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2010 Dec;16(12):2090–2098.
  • Toedter G, Li K, Marano C, et al. Gene expression profiling and response signatures associated with differential responses to infliximab treatment in ulcerative colitis. Am J Gastroenterol. 2011 Jul;106(7):1272–80.
  • Telesco SE, Brodmerkel C, Zhang H, et al. Gene expression signature for prediction of golimumab response in a phase 2a open-label trial of patients with ulcerative colitis. Gastroenterology. 2018 Oct;155(4):1008–1011 e8.
  • Sands B, Winston B, Salzberg B, et al. Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn’s disease. Aliment Pharmacol Ther. 2002;16(3):399–406. doi: 10.1046/j.1365-2036.2002.01179.x
  • West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Med. 2017 May;23(5):579–589.
  • Verstockt S, Verstockt B, Machiels K, et al. Oncostatin M is a biomarker of diagnosis, worse disease prognosis, and therapeutic nonresponse in inflammatory bowel disease. Inflamm Bowel Dis. 2021 Oct 18;27(10):1564–1575. doi: 10.1093/ibd/izab032
  • Ezirike Ladipo J, He Z, Chikwava K, et al. Oncostatin-M does not predict treatment response in inflammatory bowel disease in a pediatric cohort. J Pediatr Gastroenterol Nutr. 2021 Sep 1;73(3):352–357. doi: 10.1097/MPG.0000000000003201
  • Guo A, Ross C, Chande N, et al. High oncostatin M predicts lack of clinical remission for patients with inflammatory bowel disease on tumor necrosis factor alpha antagonists. Sci Rep. 2022 Jan 24;12(1):1185. doi: 10.1038/s41598-022-05208-9
  • Li Y, Yang X, Yuan JN, et al. Ilex rotunda thunb protects against dextran sulfate sodium-induced ulcerative colitis in mice by restoring the intestinal mucosal barrier and modulating the oncostatin m/oncostatin m receptor pathway. Front Pharmacol. 2022;13:819826. doi: 10.3389/fphar.2022.819826
  • Cao Y, Dai Y, Zhang L, et al. Combined use of fecal biomarkers in inflammatory bowel diseases: oncostatin m and calprotectin. J Inflamm Res. 2021;14:6409–6419. doi: 10.2147/JIR.S342846
  • Zhao Q, Zhang T, Yang H. ScRNA-seq identified the metabolic reprogramming of human colonic immune cells in different locations and disease states. Biochem Biophys Res Commun. 2022 May 14;604:96–103. doi: 10.1016/j.bbrc.2022.03.034
  • McLean MH, Andrews C, Hanson ML, et al. Interleukin-27 is a potential rescue therapy for acute severe colitis through interleukin-10-dependent, T-Cell-independent attenuation of colonic mucosal innate immune responses. Inflamm Bowel Dis. 2017 Nov;23(11):1983–1995.
  • Wang L, Cao J, Li C, et al. IL-27/IL-27 receptor signaling provides protection in clostridium difficile-induced colitis. J Infect Dis. 2018 Jan 4;217(2):198–207. doi: 10.1093/infdis/jix581
  • Cui B, Lu S, Lai L, et al. Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells. Oncoimmunology. 2017;6(2):e1268309. doi: 10.1080/2162402X.2016.1268309
  • Zhu X, Liu Z, Liu JQ, et al. Systemic delivery of IL-27 by an adeno-associated viral vector inhibits T cell-mediated colitis and induces multiple inhibitory pathways in T cells. J Leukoc Biol. 2016 Aug;100(2):403–11.
  • Hanson ML, Hixon JA, Li W, et al. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology. 2014 Jan;146(1):210–221 e13.
  • Troy AE, Zaph C, Du Y, et al. IL-27 regulates homeostasis of the intestinal CD4+ effector T cell pool and limits intestinal inflammation in a murine model of colitis. J Immunol. 2009 Aug 1;183(3):2037–44. doi: 10.4049/jimmunol.0802918
  • Honda K, Nakamura K, Matsui N, et al. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis. Inflamm Bowel Dis. 2005 Dec;11(12):1044–1052.
  • Furuzawa Carballeda J, Fonseca Camarillo G, Yamamoto-Furusho JK. Interleukin 27 is up-regulated in patients with active inflammatory bowel disease. Immunol Res. 2016 Aug;64(4):901–7. doi: 10.1007/s12026-016-8804-z
  • Zhang YF, Zhao AD. Common polymorphisms in IL-27 genes may contribute to risk of various human diseases in asian populations: a meta-analysis. Med Sci Monit. 2016 Mar 7;22:766–75. doi: 10.12659/MSM.895558
  • Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. 2009 Dec;41(12):1335–40.
  • Wang Z, Wang L, Fan R, et al. Association of IL-27 gene three polymorphisms with Crohn’s disease susceptibility in a Chinese Han population. Int J Clin Exp Pathol. 2014;7(12):8952–8957.
  • Li CS, Zhang Q, Lee KJ, et al. Interleukin-27 polymorphisms are associated with inflammatory bowel diseases in a Korean population. J Gastroenterol Hepatol. 2009 Oct;24(10):1692–6.
  • Vecchiarelli HA, Aukema RJ, Hume C, et al. Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice. Front Cell Neurosci. 2021;15:764706. doi: 10.3389/fncel.2021.764706
  • Guo J, Zhang R, Zhao Y, et al. MiRNA-29c-3p promotes intestinal inflammation via targeting leukemia inhibitory factor in ulcerative colitis. J Inflamm Res. 2021;14:2031–2043. doi: 10.2147/JIR.S302832
  • Guimbaud R, Abitbol V, Bertrand V, et al. Leukemia inhibitory factor involvement in human ulcerative colitis and its potential role in malignant course. Eur Cytokine Netw. 1998 Dec;9(4):607–612.
  • Zhang YS, Xin DE, Wang Z, et al. STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation. EMBO J. 2019 Mar 15;38(6):1–20. doi: 10.15252/embj.201899595
  • Prieto-Vicente V, Sanchez-Garrido AI, Blanco-Gozalo V, et al. Cardiotrophin-1 attenuates experimental colitis in mice. Clin Sci (Lond). 2018 May 23;132(9):985–1001. doi: 10.1042/CS20171513
  • Sanchez-Garrido AI, Prieto-Vicente V, Blanco-Gozalo V, et al. Preventive effect of cardiotrophin-1 administration before dss-induced ulcerative colitis in mice. J Clin Med. 2019 Dec 1;8(12):2086. doi: 10.3390/jcm8122086
  • Dambacher J, Beigel F, Seiderer J, et al. Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is upregulated in inflammatory bowel disease. Gut. 2007 Sep;56(9):1257–65.
  • Lokau J, Garbers Y, Grotzinger J, et al. A single aromatic residue in sgp130Fc/olamkicept allows the discrimination between interleukin-6 and interleukin-11 trans-signaling. iScience. 2021 Nov 19;24(11):103309. doi: 10.1016/j.isci.2021.103309
  • Heise D, Derrac Soria A, Hansen S, et al. Selective inhibition of IL-6 trans-signaling by a miniaturized, optimized chimeric soluble gp130 inhibits TH17 cell expansion. Sci Signal. 2021 Aug 17;14(696):eabc3480. doi: 10.1126/scisignal.abc3480

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.