Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice

Autoři: Wei-Wen Lim aff001;  Benjamin Ng aff001;  Anissa Widjaja aff002;  Chen Xie aff001;  Liping Su aff001;  Nicole Ko aff002;  Sze-Yun Lim aff001;  Xiu-Yi Kwek aff001;  Stella Lim aff002;  Stuart Alexander Cook aff001;  Sebastian Schafer aff001
Působiště autorů: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore aff001;  Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore aff002;  National Heart and Lung Institute, Imperial College London, London, England, United Kingdom aff003;  MRC-London Institute of Medical Sciences, London, England, United Kingdom aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including the heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn’s disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.

Klíčová slova:

Collagens – Colon – Fibrosis – Histology – Inflammation – Inflammatory bowel disease – Kidneys – Mouse models


1. Owens GK, Kumar MS, Wamhoff BR. Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease. Physiological Reviews. 2004. pp. 767–801. doi: 10.1152/physrev.00041.2003 15269336

2. Johnson PR, Roth M, Tamm M, Hughes M, Ge Q, King G, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med. 2001;164: 474–477. doi: 10.1164/ajrccm.164.3.2010109 11500353

3. Shea-Donohue T, Notari L, Sun R, Zhao A. Mechanisms of smooth muscle responses to inflammation. Neurogastroenterology & Motility. 2012. pp. 802–811. doi: 10.1111/j.1365-2982.2012.01986.x 22908862

4. Herrick AL. Vascular function in systemic sclerosis. Current Opinion in Rheumatology. 2000. pp. 527–533. doi: 10.1097/00002281-200011000-00009 11092203

5. Shin JY, Beckett JD, Bagirzadeh R, Creamer TJ, Shah AA, McMahan Z, et al. Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis. Science Translational Medicine. 2019. p. eaaw0790. doi: 10.1126/scitranslmed.aaw0790 31217334

6. Denton CP, Ong VH, Xu S, Chen-Harris H, Modrusan Z, Lafyatis R, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77: 1362–1371. doi: 10.1136/annrheumdis-2018-213031 29853453

7. Leask A, Abraham DJ. TGF-β signaling and the fibrotic response. The FASEB Journal. 2004. pp. 816–827. doi: 10.1096/fj.03-1273rev 15117886

8. Schafer S, Viswanathan S, Widjaja AA, Lim W-W, Moreno-Moral A, DeLaughter DM, et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017;552: 110–115. doi: 10.1038/nature24676 29160304

9. Ng B, Dong J, Viswanathan S, D’Agostino G, Widjaja AA, Lim W-W, et al. IL-11 is a therapeutic target in idiopathic pulmonary fibrosis. doi: 10.1101/336537

10. Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, et al. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Non-Alcoholic Steatohepatitis. Gastroenterology. 2019. 31078624

11. Taki H, Sakai T, Sugiyama E, Mino T, Kuroda A, Taki K, et al. Monokine stimulation of interleukin-11 production by human vascular smooth muscle cells in vitro. Atherosclerosis. 1999;144: 375–380. doi: 10.1016/s0021-9150(99)00009-x 10407498

12. Arijs I, Li K, Toedter G, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58: 1612–1619. doi: 10.1136/gut.2009.178665 19700435

13. Smillie CS, Biton M, Ordovas-Montañes J, Sullivan KM, Burgin G, Graham DB, et al. Rewiring of the cellular and inter-cellular landscape of the human colon during ulcerative colitis. doi: 10.1101/455451

14. Minshall E, Chakir J, Laviolette M, Molet S, Zhu Z, Olivenstein R, et al. IL-11 expression is increased in severe asthma: association with epithelial cells and eosinophils. J Allergy Clin Immunol. 2000;105: 232–238. doi: 10.1016/s0091-6749(00)90070-8 10669841

15. Wirth A, Benyó Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, et al. G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med. 2008;14: 64–68. doi: 10.1038/nm1666 18084302

16. Zheng B, Zhang Z, Black CM, de Crombrugghe B, Denton CP. Ligand-dependent genetic recombination in fibroblasts: a potentially powerful technique for investigating gene function in fibrosis. Am J Pathol. 2002;160: 1609–1617. doi: 10.1016/S0002-9440(10)61108-X 12000713

17. Wang S, Song R, Wang Z, Jing Z, Wang S, Ma J. S100A8/A9 in Inflammation. Frontiers in Immunology. 2018. doi: 10.3389/fimmu.2018.01298 29942307

18. Konikoff MR, Denson LA. Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease. Inflammatory Bowel Diseases. 2006. pp. 524–534. doi: 10.1097/00054725-200606000-00013 16775498

19. Dahab GM, Kheriza MM, El-Beltagi HM, Fouda A-MM, Sharaf El-Din OA. Digital quantification of fibrosis in liver biopsy sections: Description of a new method by Photoshop software. Journal of Gastroenterology and Hepatology. 2004. pp. 78–85. doi: 10.1111/j.1440-1746.2004.03183.x 14675247

20. Sundblad V, Quintar AA, Morosi LG, Niveloni SI, Cabanne A, Smecuol E, et al. Galectins in Intestinal Inflammation: Galectin-1 Expression Delineates Response to Treatment in Celiac Disease Patients. Front Immunol. 2018;9: 379. doi: 10.3389/fimmu.2018.00379 29545799

21. Dong S, Hughes RC. Macrophage surface glycoproteins binding to galectin-3 (Mac-2-antigen). Glycoconj J. 1997;14: 267–274. doi: 10.1023/a:1018554124545 9111144

22. Kim H, Lee J, Hyun J, Park J, Joo H, Shin T. Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Cell Biology International. 2007. pp. 655–662. doi: 10.1016/j.cellbi.2006.11.036 17222570

23. Díaz-Alvarez L, Ortega E. The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens. Mediators Inflamm. 2017;2017: 9247574. doi: 10.1155/2017/9247574 28607536

24. Taga T, Kishimoto T. gp130 AND THE INTERLEUKIN-6 FAMILY OF CYTOKINES. Annual Review of Immunology. 1997. pp. 797–819. doi: 10.1146/annurev.immunol.15.1.797 9143707

25. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Current Opinion in Cell Biology. 1995. pp. 728–735. doi: 10.1016/0955-0674(95)80116-2 8573349

26. Rossi J-F, Lu Z-Y, Jourdan M, Klein B. Interleukin-6 as a therapeutic target. Clin Cancer Res. 2015;21: 1248–1257. doi: 10.1158/1078-0432.CCR-14-2291 25589616

27. Mazzucchelli L, Hauser C, Zgraggen K, Wagner HE, Hess MW, Laissue JA, et al. Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease. J Pathol. 1996;178: 201–206. doi: 10.1002/(SICI)1096-9896(199602)178:2<201::AID-PATH440>3.0.CO;2-4 8683390

28. Grimm MC, Elsbury SK, Pavli P, Doe WF. Enhanced expression and production of monocyte chemoattractant protein-1 in inflammatory bowel disease mucosa. J Leukoc Biol. 1996;59: 804–812. doi: 10.1002/jlb.59.6.804 8691064

29. Bandinelli F, Del Rosso A, Gabrielli A, Giacomelli R, Bartoli F, Guiducci S, et al. CCL2, CCL3 and CCL5 chemokines in systemic sclerosis: the correlation with SSc clinical features and the effect of prostaglandin E1 treatment. Clin Exp Rheumatol. 2012;30: S44–9.

30. Hasegawa M, Sato S, Fujimoto M, Ihn H, Kikuchi K, Takehara K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol. 1998;25: 308–313. 9489824

31. Diaz-Granados N, Howe K, Lu J, McKay DM. Dextran Sulfate Sodium-Induced Colonic Histopathology, but not Altered Epithelial Ion Transport, Is Reduced by Inhibition of Phosphodiesterase Activity. The American Journal of Pathology. 2000. pp. 2169–2177. doi: 10.1016/S0002-9440(10)65087-0 10854237

32. Arijs I, Li K, Toedter G, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58: 1612–1619. doi: 10.1136/gut.2009.178665 19700435

33. Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell. 2019;178: 714–730.e22. doi: 10.1016/j.cell.2019.06.029 31348891

34. Arijs I, Quintens R, Van Lommel L, Van Steen K, De Hertogh G, Lemaire K, et al. Predictive value of epithelial gene expression profiles for response to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2010;16: 2090–2098. doi: 10.1002/ibd.21301 20848504

35. Qiu BS, Pfeiffer CJ, Keith JC Jr. Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci. 1996;41: 1625–1630. doi: 10.1007/bf02087911 8769290

36. Gibson DL, Montero M, Ropeleski MJ, Bergstrom KSB, Ma C, Ghosh S, et al. Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology. 2010;139: 1277–1288. doi: 10.1053/j.gastro.2010.06.057 20600022

37. Orazi A, Du X, Yang Z, Kashai M, Williams DA. Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation. Lab Invest. 1996;75: 33–42. 8683938

38. Boerma M, Wang J, Burnett AF, Santin AD, Roman JJ, Hauer-Jensen M. Local administration of interleukin-11 ameliorates intestinal radiation injury in rats. Cancer Res. 2007;67: 9501–9506. doi: 10.1158/0008-5472.CAN-07-0810 17909060

39. Widjaja AA, Dong J, Adami E, Viswanathan S, Ng B, Singh BK, et al. Redefining Interleukin 11 as a regeneration-limiting hepatotoxin. doi: 10.1101/830018

40. Elias JA, Wu Y, Zheng T, Panettieri R. Cytokine- and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines. Am J Physiol. 1997;273: L648–55. doi: 10.1152/ajplung.1997.273.3.L648 9316501

41. Shi X-Z, Sarna SK. Transcriptional regulation of inflammatory mediators secreted by human colonic circular smooth muscle cells. Am J Physiol Gastrointest Liver Physiol. 2005;289: G274–84. doi: 10.1152/ajpgi.00512.2004 15790759

42. Jin B-R, Chung K-S, Cheon S-Y, Lee M, Hwang S, Noh Hwang S, et al. Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-κB and STAT3 activation. Sci Rep. 2017;7: 46252. doi: 10.1038/srep46252 28383063

43. DeRoche TC, Xiao S-Y, Liu X. Histological evaluation in ulcerative colitis. Gastroenterology Report. 2014. pp. 178–192. doi: 10.1093/gastro/gou031 24942757

44. de Bruyn JR, Meijer SL, Wildenberg ME, Bemelman WA, van den Brink GR, D’Haens GR. Development of Fibrosis in Acute and Longstanding Ulcerative Colitis. J Crohns Colitis. 2015;9: 966–972. doi: 10.1093/ecco-jcc/jjv133 26245217

45. Lakhan SE, Kirchgessner A. Neuroinflammation in inflammatory bowel disease. Journal of Neuroinflammation. 2010. p. 37. doi: 10.1186/1742-2094-7-37 20615234

46. Chen W, Lu C, Hirota C, Iacucci M, Ghosh S, Gui X. Smooth Muscle Hyperplasia/Hypertrophy is the Most Prominent Histological Change in Crohn’s Fibrostenosing Bowel Strictures: A Semiquantitative Analysis by Using a Novel Histological Grading Scheme. Journal of Crohn’s and Colitis. 2017. pp. 92–104. doi: 10.1093/ecco-jcc/jjw126 27364949

47. Collins SM, Khan I, Vallance B, Hogaboam C. The role of smooth muscle in intestinal inflammation. Inflammatory Bowel Disease. 1994. pp. 162–169. doi: 10.1007/978-94-009-0371-5_16

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden