Journal Article
. 2013 Aug; 8(8):e72594.
doi: 10.1371/journal.pone.0072594.

Intestinal-specific TNFα overexpression induces Crohn's-like ileitis in mice

Giorgos Bamias 1 Mohamed I Dahman  Kristen O Arseneau  Mitchell Guanzon  Dennis Gruska  Theresa T Pizarro  Fabio Cominelli  
  • PMID: 23977323
  •     33 References
  •     14 citations


Background And Aim: Human and animal studies have clearly established tumor necrosis factor (TNF)α as an important mediator of Crohn's disease pathogenesis. However, whether systemic or only local TNFα overproduction is required for the development of chronic intestinal inflammation and Crohn's disease remains unclear. The aim of this study was to assess the contribution of intestinal epithelial-derived TNFα to the development of murine Crohn's-like ileitis.

Methods: We adapted the well-established TNF(∆ARE/+) mouse model of Crohn's disease (which systemically overexpresses TNFα) to generate a homozygous mutant strain that overexpress TNFα only within the intestinal epithelium. Intestinal-specific TNF(i∆ARE/i∆ARE) mice were examined for histopathological signs of gut inflammation and extraintestinal manifestations of Crohn's disease. The mucosal immune phenotype was characterized, and the contribution of specific lymphocyte populations to the pathogenesis of TNF(i∆ARE/i∆ARE) ileitis was assessed.

Results: TNF(i∆ARE/i∆ARE) mice had increased mucosal and systemic TNFα levels compared to wild-type controls (P<0.001), as well as severe chronic ileitis with increased neutrophil infiltration and villous distortion, but no extraintestinal manifestations (P<0.001 vs. wild-type controls). The gut mucosal lymphocytic compartment was also expanded in TNF(i∆ARE/i∆ARE) mice (P<0.05), consisting of activated CD69(+) and CD4(+)CD62L(-) lymphocytes (P<0.05). FasL expression was significantly elevated in the mesenteric lymph nodes of TNF(i∆ARE/i∆ARE) mice (P<0.05). Adoptive transfer of mucosal TNF(i∆ARE/i∆ARE) lymphocytes resulted in ileitis in immunologically naïve severe combined immunodeficiency recipients (P<0.05 vs. wild-type controls), indicating an effector phenotype that was associated with increased production of both Th1 (IFNγ) and Th2 (IL-5, IL-13) cytokines.

Conclusion: Intestinal epithelial-derived TNFα is sufficient for the induction of Crohn's-like ileitis, but not for the occurrence of extraintestinal manifestations, in TNF(i∆ARE/i∆ARE) mice. These effects were associated with generation of effector lymphocytes within the intestinal mucosa and dysregulated apoptosis. Thus, targeted intestinal blockade of TNFα may provide an effective means to neutralize gut-derived TNFα with reduced side effects.

Distinct inflammatory mechanisms mediate early versus late colitis in mice.
David M Spencer, Geertruida M Veldman, +2 authors, Alan D Levine.
Gastroenterology, 2002 Jan 10; 122(1). PMID: 11781285
Role of cytokines in the pathogenesis of inflammatory bowel disease.
K A Papadakis, S R Targan.
Annu Rev Med, 2000 Apr 25; 51. PMID: 10774465
Highly Cited. Review.
Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease.
M M Kosiewicz, C C Nast, +5 authors, F Cominelli.
J Clin Invest, 2001 Mar 20; 107(6). PMID: 11254669    Free PMC article.
Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma.
Iris Dotan, Matthieu Allez, +3 authors, Lloyd Mayer.
Am J Physiol Gastrointest Liver Physiol, 2007 Mar 10; 292(6). PMID: 17347451
Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.
H C Rath, H H Herfarth, +7 authors, R B Sartor.
J Clin Invest, 1996 Aug 15; 98(4). PMID: 8770866    Free PMC article.
Highly Cited.
Cellular localization of tumor necrosis factor (TNF)-alpha transcripts in normal bowel and in necrotizing enterocolitis. TNF gene expression by Paneth cells, intestinal eosinophils, and macrophages.
X Tan, W Hsueh, F Gonzalez-Crussi.
Am J Pathol, 1993 Jun 01; 142(6). PMID: 8506954    Free PMC article.
Infliximab for induction and maintenance therapy for ulcerative colitis.
Paul Rutgeerts, William J Sandborn, +11 authors, Jean Frédéric Colombel.
N Engl J Med, 2005 Dec 13; 353(23). PMID: 16339095
Highly Cited.
A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion.
H C Jung, L Eckmann, +4 authors, M F Kagnoff.
J Clin Invest, 1995 Jan 01; 95(1). PMID: 7814646    Free PMC article.
Highly Cited.
Translational blockade imposed by cytokine-derived UA-rich sequences.
V Kruys, O Marinx, +2 authors, G Huez.
Science, 1989 Aug 25; 245(4920). PMID: 2672333
Highly Cited.
Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome.
Dirk Raddatz, Miriam Bockemühl, Giuliano Ramadori.
Eur J Gastroenterol Hepatol, 2005 Apr 14; 17(5). PMID: 15827446
Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice.
M F Neurath, I Fuss, +5 authors, G Kollias.
Eur J Immunol, 1997 Jul 01; 27(7). PMID: 9247586
Highly Cited.
Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis.
Jesús Rivera-Nieves, Giorgos Bamias, +6 authors, Fabio Cominelli.
Gastroenterology, 2003 Apr 03; 124(4). PMID: 12671894
Epithelial NEMO links innate immunity to chronic intestinal inflammation.
Arianna Nenci, Christoph Becker, +10 authors, Manolis Pasparakis.
Nature, 2007 Mar 16; 446(7135). PMID: 17361131
Highly Cited.
New concepts in the pathophysiology of inflammatory bowel disease.
Giorgos Bamias, Mark R Nyce, +3 authors, American Physiological Society.
Ann Intern Med, 2005 Dec 21; 143(12). PMID: 16365470
Probiotics promote gut health through stimulation of epithelial innate immunity.
Cristiano Pagnini, Rubina Saeed, +3 authors, Fabio Cominelli.
Proc Natl Acad Sci U S A, 2009 Dec 19; 107(1). PMID: 20018654    Free PMC article.
Highly Cited.
TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality.
Emiko Mizoguchi, Yuriko Hachiya, +5 authors, Daniel K Podolsky.
Gastroenterology, 2008 Feb 05; 134(2). PMID: 18242213
The primary defect in experimental ileitis originates from a nonhematopoietic source.
Timothy S Olson, Brian K Reuter, +10 authors, Theresa T Pizarro.
J Exp Med, 2006 Mar 01; 203(3). PMID: 16505137    Free PMC article.
Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naïve ulcerative colitis during active and quiescent disease.
Reikei Matsuda, Tomoko Koide, +8 authors, Satoshi Umemura.
Inflamm Bowel Dis, 2008 Oct 24; 15(3). PMID: 18942752
Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
Erik-Oliver Glocker, Daniel Kotlarz, +25 authors, Christoph Klein.
N Engl J Med, 2009 Nov 06; 361(21). PMID: 19890111    Free PMC article.
Highly Cited.
Adalimumab for the treatment of fistulas in patients with Crohn's disease.
J-F Colombel, D A Schwartz, +10 authors, P F Pollack.
Gut, 2009 Feb 10; 58(7). PMID: 19201775    Free PMC article.
AU-rich elements: characterization and importance in mRNA degradation.
C Y Chen, A B Shyu.
Trends Biochem Sci, 1995 Nov 01; 20(11). PMID: 8578590
Highly Cited. Review.
Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.
Rie Kajino-Sakamoto, Maiko Inagaki, +5 authors, Jun Ninomiya-Tsuji.
J Immunol, 2008 Jul 09; 181(2). PMID: 18606667    Free PMC article.
Intestinal epithelial cells as producers but not targets of chronic TNF suffice to cause murine Crohn-like pathology.
Manolis Roulis, Maria Armaka, +2 authors, George Kollias.
Proc Natl Acad Sci U S A, 2011 Mar 16; 108(13). PMID: 21402942    Free PMC article.
Natalizumab induction and maintenance therapy for Crohn's disease.
William J Sandborn, Jean Frédéric Colombel, +14 authors, Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group.
N Engl J Med, 2005 Nov 04; 353(18). PMID: 16267322
Highly Cited.
TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis.
Marco Marini, Giorgos Bamias, +5 authors, Fabio Cominelli.
Proc Natl Acad Sci U S A, 2003 Jul 02; 100(14). PMID: 12832622    Free PMC article.
Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice.
Yuji Naito, Tomohisa Takagi, +8 authors, Toshikazu Yoshikawa.
J Gastroenterol Hepatol, 2003 Apr 19; 18(5). PMID: 12702049
A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.
S R Targan, S B Hanauer, +6 authors, P J Rutgeerts.
N Engl J Med, 1997 Oct 09; 337(15). PMID: 9321530
Highly Cited.
Inducible gene knockouts in the small intestinal and colonic epithelium.
J R Saam, J I Gordon.
J Biol Chem, 1999 Dec 23; 274(53). PMID: 10608876
Downregulation of epithelial apoptosis and barrier repair in active Crohn's disease by tumour necrosis factor alpha antibody treatment.
S Zeissig, C Bojarski, +4 authors, J D Schulzke.
Gut, 2004 Aug 13; 53(9). PMID: 15306588    Free PMC article.
Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation.
Giorgos Bamias, Charles Martin, +4 authors, Fabio Cominelli.
Gastroenterology, 2005 Mar 15; 128(3). PMID: 15765401
Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial.
W J Sandborn, S B Hanauer, +9 authors, P F Pollack.
Gut, 2007 Feb 15; 56(9). PMID: 17299059    Free PMC article.
Highly Cited.
The TNF and TNF receptor superfamilies: integrating mammalian biology.
R M Locksley, N Killeen, M J Lenardo.
Cell, 2001 Mar 10; 104(4). PMID: 11239407
Highly Cited. Review.
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies.
D Kontoyiannis, M Pasparakis, +2 authors, G Kollias.
Immunity, 1999 Apr 16; 10(3). PMID: 10204494
Highly Cited.
TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle.
Craig L Doig, Jamila Bashir, +3 authors, Gareth G Lavery.
J Endocrinol, 2014 Jan 15; 220(3). PMID: 24413279    Free PMC article.
Cytokines and mucosal immunity.
Giorgos Bamias, Kristen O Arseneau, Fabio Cominelli.
Curr Opin Gastroenterol, 2014 Sep 10; 30(6). PMID: 25203451    Free PMC article.
Intestinal epithelium in inflammatory bowel disease.
Mehmet Coskun.
Front Med (Lausanne), 2015 Jan 17; 1. PMID: 25593900    Free PMC article.
Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.
Monika Schaubeck, Thomas Clavel, +9 authors, Dirk Haller.
Gut, 2015 Apr 19; 65(2). PMID: 25887379    Free PMC article.
Highly Cited.
Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line.
Keita Fukushima, Kiichiro Tsuchiya, +13 authors, Mamoru Watanabe.
Cancer Sci, 2015 May 29; 106(8). PMID: 26017781    Free PMC article.
Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes.
Alex Rodriguez-Palacios, Tomohiro Kodani, +7 authors, Fabio Cominelli.
Nat Commun, 2015 Jul 15; 6. PMID: 26154811    Free PMC article.
Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection.
Ludovica F Buttó, Monika Schaubeck, Dirk Haller.
Front Immunol, 2015 Dec 05; 6. PMID: 26635787    Free PMC article.
Reduced stress and inflammatory responsiveness in experienced meditators compared to a matched healthy control group.
Melissa A Rosenkranz, Antoine Lutz, +4 authors, Richard J Davidson.
Psychoneuroendocrinology, 2016 Mar 14; 68. PMID: 26970711    Free PMC article.
Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn's Disease-Like Ileitis: What is the Right Model?
Fabio Cominelli, Kristen O Arseneau, Alexander Rodriguez-Palacios, Theresa T Pizarro.
Cell Mol Gastroenterol Hepatol, 2017 Jun 01; 4(1). PMID: 28560286    Free PMC article.
Cytokine production profile in intestinal mucosa of paediatric inflammatory bowel disease.
Serena Vitale, Caterina Strisciuglio, +10 authors, Carmen Gianfrani.
PLoS One, 2017 Aug 11; 12(8). PMID: 28797042    Free PMC article.
Death-Domain-Receptor 3 Deletion Normalizes Inflammatory Gene Expression and Prevents Ileitis in Experimental Crohn's Disease.
Ludovica F Buttó, Li-Guo Jia, +7 authors, Fabio Cominelli.
Inflamm Bowel Dis, 2018 Oct 09; 25(1). PMID: 30295722    Free PMC article.
The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues.
Joshua D Webster, Domagoj Vucic.
Front Cell Dev Biol, 2020 Jul 17; 8. PMID: 32671059    Free PMC article.
Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease.
L Schulte, M Hohwieler, M Müller, J Klaus.
Stem Cells Int, 2019 Apr 25; 2019. PMID: 31015842    Free PMC article.
Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities.
Victoria A Blaho.
Adv Exp Med Biol, 2020 Sep 08; 1274. PMID: 32894509