Insights into TL1A and IBD Pathogenesis

  • David Q. Shih
  • Kathrin S. Michelsen
  • Robert J. Barrett
  • Eva Biener-Ramanujan
  • Rivkah Gonsky
  • Xiaolan Zhang
  • Stephan R. Targan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders caused by dysregulated immune responses to microbial antigens in a genetically predisposed individual. Recent and accumulating research, including genome-wide association studies (GWAS), has identified over 50 distinct genetic loci that confer susceptibility and begin to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. Among the several recently discovered IBD associated gene variants in tumor necrosis factor superfamily member 15 (TNFSF15) has been shown to be associated with CD in all ethnic and age groups. TL1A is the product of the TNFSF15 gene and signals through death receptor 3 (DR3). Among the evidence indicating an important functional role of TL1A in mediating gut mucosal inflammation is the finding that neutralizing antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models. In addition, TL1A expression is elevated in lamina propria mononuclear cells (LPMC) from the mucosa of IBD patients and varies in association with different CD genotypes, as defined by ethnic background, haplotype, and serum microbial antibody expression. One of the etiologic theories on the pathogenesis of IBD is that impaired clearance of foreign material leads to a sustained activation of antigen presenting cells and a compensatory induction of an adaptive immune response. Consistent with the important role of TL1A in IBD, microbial organisms and FcγR signaling induce TL1A in myeloid cells leading to enhanced Th1 responses. These and other studies define TL1A as a master regulatory cytokine that plays a key role in human intestinal inflammation.


Inflammatory Bowel Disease Inflammatory Bowel Disease Patient Pediatric Inflammatory Bowel Disease Inflammatory Bowel Disease Susceptibility Pediatric Inflammatory Bowel Disease Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Support for this work was provided by USPHS grants NIH DK046763 and NIH DK056328. We thank Loren C. Karp for critical reading of this manuscript.


  1. 1.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756CrossRefPubMedGoogle Scholar
  2. 2.
    Arnott ID et al (2004) Sero-reactivity to microbial components in Crohn’s disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol 99:2376–2384CrossRefPubMedGoogle Scholar
  3. 3.
    Bamias G et al (2003) Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol 171:4868–4874PubMedGoogle Scholar
  4. 4.
    Barrett JC et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40:955–962CrossRefPubMedGoogle Scholar
  5. 5.
    Brand S et al (2006) IL-22 is increased in active Crohn’s n disease and promotes proinflammatory gene expression and intestinal epithelia cell migration. Am J Physiol Gastrointest Liver Physiol 290:G827–G838CrossRefPubMedGoogle Scholar
  6. 6.
    Bull MJ et al (2008) The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J Exp Med 205:2457–2464CrossRefPubMedGoogle Scholar
  7. 7.
    Cassatella MA et al (2007) Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. J Immunol 178:7325–7333PubMedGoogle Scholar
  8. 8.
    Cohavy O, Zhou J, Granger SW, Ware CF, Targan SR (2004) LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine. J Immunol 173:251–258PubMedGoogle Scholar
  9. 9.
    Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9:271–285CrossRefPubMedGoogle Scholar
  10. 10.
    Endo K, Kinouchi Y, Kakuta Y, Ueki N, Takahashi S, Shimosegawa T (2009) Involvement of NF-kappa B pathway in TL1A gene expression induced by lipopolysaccharide. CytokineGoogle Scholar
  11. 11.
    Fang L, Adkins B, Deyev V, Podack ER (2008) Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J Exp Med 205:1037–1048CrossRefPubMedGoogle Scholar
  12. 12.
    Fujino S et al (2003) Increased exprossion of interleukin 17 in inflammatory bowel disease. Gut 52:65–70CrossRefPubMedGoogle Scholar
  13. 13.
    Furuya D et al (2002) Serum interlcukin-18 concentrations in patients with inflammatory bowel disease. J Immunother 25(Suppl 1):S65–S67CrossRefPubMedGoogle Scholar
  14. 14.
    Kakuta Y, Kinouchi Y, Negoro K, Takahashi S, Shimosegawa T (2006) Association study of TNFSF15 polymorphisms in Japanese patients with inflammatory bowel disease. Gut 55:1527–1528CrossRefPubMedGoogle Scholar
  15. 15.
    Kakuta Y et al (2009) TNFSF15 transcripts from risk haplotype for Crohn’s disease are overexpressed in stimulated T cells. Hum Mol Genet 18:1089–1098CrossRefPubMedGoogle Scholar
  16. 16.
    Kugathasan S et al (2008) Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 40:1211–1215CrossRefPubMedGoogle Scholar
  17. 17.
    Meylan F et al (2008) The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29:79–89CrossRefPubMedGoogle Scholar
  18. 18.
    Michelsen KS et al (2009) IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One 4:e4719CrossRefPubMedGoogle Scholar
  19. 19.
    Migone TS et al (2002) TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16:479–492CrossRefPubMedGoogle Scholar
  20. 20.
    Monteleone G et al (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastrocnterology 128:687–694CrossRefGoogle Scholar
  21. 21.
    Mow WS et al (2004) Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology 126:414–424CrossRefPubMedGoogle Scholar
  22. 22.
    Niclson OH, Rudiger N, Gaustadnes M, Horn T (1997) Intestinal interleukin-8 concentration and gene expression in inflammatory bowel disease. Scand J Gastroenterol 32:1028–1034CrossRefGoogle Scholar
  23. 23.
    Papadakis KA et al (2003) CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile. J Immunol 171:159–165PubMedGoogle Scholar
  24. 24.
    Papadakis KA et al (2004) TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells. J Immunol 172:7002–7007PubMedGoogle Scholar
  25. 25.
    Papadakis KA et al (2005) Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. J Immunol 174:4985–4990PubMedGoogle Scholar
  26. 26.
    Pappu BP et al (2008) TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med 205:1049–1062CrossRefPubMedGoogle Scholar
  27. 27.
    Picornell Y, Mei L, Taylor K, Yang H, Targan SR, Rotter JI (2007) TNFSF15 is an ethnic-specific IBD gene. Inflamm Bowel Dis 13:1333–1338CrossRefPubMedGoogle Scholar
  28. 28.
    Prehn JL et al (2004) Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol 112:66–77CrossRefPubMedGoogle Scholar
  29. 29.
    Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR (2007) The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. J Immunol 178:4033–4038PubMedGoogle Scholar
  30. 30.
    Raddatz D, Bockemuhl M, Ramadori G (2005) Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome. Eur J Gastroenterol Hepatol 17:547–557CrossRefPubMedGoogle Scholar
  31. 31.
    Rutgeerts P et al (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353:2462–2476CrossRefPubMedGoogle Scholar
  32. 32.
    Saruta M, Michelsen KS, Thomas LS, Yu QT, Landers CJ, Targan SR (2009a) TLR8-mediated activation of human monocytes inhibits TL1A expression. Eur J Immunol 39:2195–2202CrossRefPubMedGoogle Scholar
  33. 33.
    Saruta M, Targan SR, Mei L, Ippoliti AF, Taylor KD, Rotter JI (2009b) High-frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in females. Inflamm Bowel Dis 15:321–327CrossRefPubMedGoogle Scholar
  34. 34.
    Schmidt C et al (2005) Expression of interleukin-12 related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm Bowel Dis 11:16–23CrossRefPubMedGoogle Scholar
  35. 35.
    Shih DQ et al (2009) Microbial induction of inflammatory bowel disease associated gene TL1A (TNFSF15) in antigen presenting cells. Eur. J. Immunol 39:3239–3250Google Scholar
  36. 36.
    Shih DQ, Targan SR (2008) Immunopathogenesis of inflammatory bowel disease. World J Gastroenterol 14:390–400CrossRefPubMedGoogle Scholar
  37. 37.
    Shih DQ, Targan SR, McGovern D (2008) Recent advances in IBD pathogenesis: genetics and immunobiology. Curr Gastroenterol Rep 10:568–575CrossRefPubMedGoogle Scholar
  38. 38.
    Takedatsu H et al (2008) TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology 135:552–567CrossRefPubMedGoogle Scholar
  39. 39.
    Tan KB et al (1997) Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 204:35–46CrossRefPubMedGoogle Scholar
  40. 40.
    Targan SR et al (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 337:1029–1035CrossRefPubMedGoogle Scholar
  41. 41.
    Tremelling M et al (2008) Contribution of TNFSF15 gene variants to Crohn’s disease susceptibility confirmed in UK population. Inflamm Bowel Dis 14:733–737CrossRefPubMedGoogle Scholar
  42. 42.
    Yamazaki K et al (2005) Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 14:3499–3506CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • David Q. Shih
    • 1
  • Kathrin S. Michelsen
    • 1
  • Robert J. Barrett
    • 1
  • Eva Biener-Ramanujan
    • 1
  • Rivkah Gonsky
    • 1
  • Xiaolan Zhang
    • 2
  • Stephan R. Targan
    • 1
  1. 1.Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical CenterLos AngelesUSA
  2. 2.Dept. of GastroenterologyThe Second Hospital of Hebei Medical UniversityShijiazhuang CityChina

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