Digestive Diseases and Sciences

, Volume 56, Issue 12, pp 3525–3533 | Cite as

Th1 Responses Are More Susceptible to Infliximab-Mediated Immunosuppression Than Th17 Responses

  • Kenji Kanayama
  • Kazuhiko Nakamura
  • Haruei Ogino
  • Yorinobu Sumida
  • Eikichi Ihara
  • Hirotada Akiho
  • Ryoichi Takayanagi
Original Article



Treatment with infliximab, a chimeric anti-tumor necrosis factor (TNF)-α antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-α and induces the apoptosis of transmembrane TNF-α-positive macrophages and T cells in the gut. Recently, T helper (Th)17, as well as Th1, responses have been implicated in the pathogenesis of IBD.


To clarify the effects of infliximab on Th1 and Th17 responses in vitro.


Naive CD4+ T cells isolated from the peripheral blood of healthy volunteers were stimulated under Th1- or Th17-inducing conditions in the presence of 10 μg/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-γ, interleukin (IL)-17, and TNF-α in the culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Th1 and Th17 cells were immunostained with infliximab or control IgG1 and transmembrane TNF-α-positive cells were analyzed by flow cytometry. Annexin V staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays were conducted in order to analyze the percentage of apoptotic cells.


Both Th1 and Th17 cells expressed soluble and transmembrane TNF-α abundantly. Although infliximab suppressed IFN-γ secretion by Th1 cells and IL-17 secretion by Th17 cells, the level of the former was more profound than the latter. Infliximab increased annexin V- and TUNEL-positive apoptotic cells under Th1-inducing conditions, but not under Th17-inducing conditions.


Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-γ production by Th1 cells was more profoundly suppressed than IL-17 secretion by Th17 cells. Th1 responses were more susceptible to infliximab-mediated apoptosis than Th17 responses. Our results clarify a new mechanism of action of infliximab.


Infliximab Tumor necrosis factor-α T helper 1 T helper 17 Apoptosis 



The authors thank Drs. Takahiro Mizutani and Hiromi Muta for their help in conducting the experiments.

Conflicts of interest

The authors have no conflicts of interest to disclose.


  1. 1.
    Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–533.PubMedCrossRefGoogle Scholar
  2. 2.
    Wynn TA. T(H)-17: a giant step from T(H)1 and T(H)2. Nat Immunol. 2005;6:1069–1070.PubMedCrossRefGoogle Scholar
  3. 3.
    Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–1132.PubMedCrossRefGoogle Scholar
  4. 4.
    Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–725.PubMedCrossRefGoogle Scholar
  5. 5.
    Aggarwal S, Ghilardi N, Xie MH, et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910–1914.PubMedCrossRefGoogle Scholar
  6. 6.
    Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–1957.PubMedCrossRefGoogle Scholar
  7. 7.
    Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–748.PubMedCrossRefGoogle Scholar
  8. 8.
    Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–240.PubMedCrossRefGoogle Scholar
  9. 9.
    Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–145.PubMedCrossRefGoogle Scholar
  10. 10.
    Hölttä V, Klemetti P, Sipponen T, et al. IL-23/IL-17 immunity as a hallmark of Crohn’s disease. Inflamm Bowel Dis. 2008;14:1175–1184.PubMedCrossRefGoogle Scholar
  11. 11.
    Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57:1682–1689.PubMedCrossRefGoogle Scholar
  12. 12.
    Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–1316.PubMedCrossRefGoogle Scholar
  13. 13.
    Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132:2359–2370.PubMedCrossRefGoogle Scholar
  14. 14.
    Targan SR, Hanauer SB, van Deventer SJ, et al. 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. 1997;337:1029–1035.PubMedCrossRefGoogle Scholar
  15. 15.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549.PubMedCrossRefGoogle Scholar
  16. 16.
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–885.PubMedCrossRefGoogle Scholar
  17. 17.
    Chey WY, Hussain A, Ryan C, et al. Infliximab for refractory ulcerative colitis. Am J Gastroenterol. 2001;96:2373–2381.PubMedCrossRefGoogle Scholar
  18. 18.
    Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol. 2002;97:2577–2584.PubMedCrossRefGoogle Scholar
  19. 19.
    Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–2476.PubMedCrossRefGoogle Scholar
  20. 20.
    Siegel SA, Shealy DJ, Nakada MT, et al. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine. 1995;7:15–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine. 1995;7:251–259.PubMedCrossRefGoogle Scholar
  22. 22.
    Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94:174–181.PubMedCrossRefGoogle Scholar
  23. 23.
    Lügering A, Schmidt M, Lügering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology. 2001;121:1145–1157.PubMedCrossRefGoogle Scholar
  24. 24.
    ten Hove T, Van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut. 2002;50:206–211.PubMedCrossRefGoogle Scholar
  25. 25.
    Van den Brande JM, Braat H, Van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology. 2003;124:1774–1785.PubMedCrossRefGoogle Scholar
  26. 26.
    Di Sabatino A, Ciccocioppo R, Cinque B, et al. Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn’s disease. Gut. 2004;53:70–77.PubMedCrossRefGoogle Scholar
  27. 27.
    Infante-Duarte C, Horton HF, Byrne MC, et al. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol. 2000;165:6107–6115.PubMedGoogle Scholar
  28. 28.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, et al. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8:942–949.PubMedCrossRefGoogle Scholar
  29. 29.
    Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115:182–205.PubMedCrossRefGoogle Scholar
  30. 30.
    Kontoyiannis D, Pasparakis M, Pizarro TT, et al. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10:387–398.PubMedCrossRefGoogle Scholar
  31. 31.
    Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8:639–646.PubMedCrossRefGoogle Scholar
  32. 32.
    Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–1197.PubMedCrossRefGoogle Scholar
  33. 33.
    Sieper J, Van Den Brande J. Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum. 2005;34:23–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kenji Kanayama
    • 1
  • Kazuhiko Nakamura
    • 1
  • Haruei Ogino
    • 1
  • Yorinobu Sumida
    • 1
  • Eikichi Ihara
    • 1
  • Hirotada Akiho
    • 1
  • Ryoichi Takayanagi
    • 1
  1. 1.Department of Medicine and Bioregulatory Science, Graduate School of Medical SciencesKyushu UniversityHigashi-kuJapan

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