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Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice
  1. K Inagaki-Ohara1,
  2. A Sasaki2,
  3. G Matsuzaki3,
  4. T Ikeda4,
  5. M Hotokezaka5,
  6. K Chijiiwa5,
  7. M Kubo6,
  8. H Yoshida7,
  9. Y Nawa8,
  10. A Yoshimura2
  1. 1Parasitic Diseases Unit, Department of Infectious Diseases, University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan, and Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
  2. 2Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
  3. 3Molecular Microbiology Group, Centre of Molecular Biosciences, University of the Ryukyus, Senbaru, Nishihara, Okinawa, Japan
  4. 4Parasitic Diseases Unit, Department of Infectious Diseases, University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan, and Department of Surgery, University of Miyazaki, Miyazaki Medical College, Kiyotake, Miyazaki, Japan
  5. 5Department of Surgery, University of Miyazaki, Miyazaki Medical College, Kiyotake, Miyazaki, Japan
  6. 6Laboratory for Signal Network, RIKEN Research Centre for Allergy and Immunology (RCAI), RIKEN Yokohama Institute, Suehiro-cho, Tsurumi, Yokohama, Kanagawa, Japan
  7. 7Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan, and PRESTO, Japan Science and Technology Corporation (JST), Kawaguchi, Saitama, Japan
  8. 8Parasitic Diseases Unit, Department of Infectious Diseases, University of Miyazaki, Kihara, Kiyotake, Miyazaki, Japan
  1. Correspondence to:
    Dr K Inagaki-Ohara
    Parasitic Diseases Unit, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; INAGAKI{at}med.miyazaki-u.ac.jp

Abstract

Background and aims: Imbalance between pro- and anti-inflammatory cytokines produced by intestinal T cells induces inflammatory bowel diseases (IBD). However, the importance of regulation of cytokine signalling in IBD has not been fully clarified. We have demonstrated that suppressor of cytokine signalling 1 (SOCS1) is expressed in inflamed tissues in an experimental colitis model. In the present study, we investigated the role of SOCS1 in colitis models to clarify the mechanism of IBD development.

Methods: Intestinal T cells in transgenic mice expressing high levels of SOCS1 in lymphocytes (SOCS1Tg mice) were characterised by flow cytometric analysis and cytokine production from intestinal T cells was determined by ELISA. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis was induced in SOCS1Tg mice and severity was compared with control littermates by measurement of survival rates. Intracellular signalling was assessed by western blotting analysis.

Results: SOCS1Tg mice developed colitis spontaneously with age. Young SOCS1Tg mice less than 15 weeks of age, before the onset of colitis, were susceptible to TNBS induced colitis. Intestinal T cells of SOCS1Tg mice showed increased interferon γ and tumour necrosis factor α production and decreased transforming growth factor β production. Expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a negative regulator of T cell activation, in SOCS1Tg mice was severely impaired at the protein level although mRNA levels of CTLA-4 in SOCS1Tg mice were comparable with those in control mice.

Conclusions: Our data suggest that SOCS1 plays an important role in the regulation of colitis by controlling intestinal T cell activation mediated through CTLA-4 expression.

  • IBD, inflammatory bowel disease
  • SOCS, suppressor of cytokine signalling
  • JAK, Janus kinase
  • STAT, signal transducers and activators of transcription
  • IEL, intestinal intraepithelial lymphocytes
  • LPL, lamina propria lymphocytes
  • EC, epithelial cells
  • TNBS, 2,4,6-trinitrobenzene sulphonic acid
  • IFN-γ, interferon γ
  • CTLA-4, cytotoxic T lymphocyte associated antigen 4
  • TCR, T cell receptor
  • TGF-β, transforming growth factor β
  • RT-PCR, reverse transcription-polymerase chain reaction
  • FACS, fluorescence activated cell sorting
  • mAb, monoclonal antibody
  • IL, interleukin
  • TNF-α, tumour necrosis factor α
  • PLCγ1, phospholipase-Cγ1
  • colitis
  • suppressor of cytokine signalling 1
  • mucosal T cell
  • CTLA-4

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Footnotes

  • Published online first 24 August 2005

  • Conflict of interest: None declared.

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