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  • T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease

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Inflammatory bowel disease
T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease
  1. K Matsuoka1,
  2. N Inoue1,
  3. T Sato1,
  4. S Okamoto1,
  5. T Hisamatsu1,
  6. Y Kishi1,
  7. A Sakuraba1,
  8. O Hitotsumatsu1,
  9. H Ogata1,
  10. K Koganei2,
  11. T Fukushima2,
  12. T Kanai3,
  13. M Watanabe3,
  14. H Ishii1,
  15. T Hibi1
  1. 1Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
  2. 2Department of Surgery, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
  3. 3Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  1. Correspondence to:
    Dr T Hibi
    Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; rei-ibdsc.itc.keio.ac.jp

Abstract

Background and aims: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn’s disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD.

Materials: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5).

Methods: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon γ (IFN-γ) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12.

Results: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-γ production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-γ production and with augmentation of surface expressed IL-12 receptor β2.

Conclusions: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.

  • CD, Crohn’s disease
  • UC, ulcerative colitis
  • NL, normal control
  • IL, interleukin
  • IL-12Rβ2, IL-12 receptor β2
  • LPMC, lamina propria mononuclear cell
  • PBMC, peripheral blood mononuclear cell
  • T-bet, T-box expressed in T cells
  • TCR, T cell receptor
  • Th1, T helper cell type 1
  • IFN-γ, interferon γ
  • mAb, monoclonal antibody
  • TNF-α, tumour necrosis factor α
  • PCR, polymerase chain reaction
  • AU, arbitrary units
  • TGF-β, transforming growth factor β
  • T-bet
  • Crohn’s disease
  • ulcerative colitis
  • interleukin 12
  • interleukin 18

https://doi.org/10.1136/gut.2003.024190

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