Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNγ and IL-4 are involved

Takatoshi Chinen, Takashi Kobayashi, Hisanobu Ogata, Giichi Takaesu, Hiromi Takaki, Masayuki Hashimoto, Hideo Yagita, Hajime Nawata, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

Background & Aims: The suppressor of cytokine signaling-1 (SOCS1) is a potent negative regulator of various cytokines and it has been implicated in the regulation of immune responses. However, the role of SOCS1 in inflammatory bowel diseases (IBDs) has not been clarified. To determine the role of SOCS1 in colitis, we generated SOCS1/T-cell receptor α (TCRα) double knockout (DKO) mice. Methods: The depletion of interferon γ (IFNγ) and IL-4 was achieved by crossing the DKO mice with IFNγ knockout (KO) mice and by the administration of anti-IL-4 antibody, respectively. The activation of cytokine-induced transcription factors was determined by Western blotting with phosphorylation-specific antibodies, and the induction of inflammatory factors was measured by reverse-transcription polymerase chain reaction. Results: Much more severe colitis developed in 100% of the DKO mice within 9 weeks of age than in TCRα-KO mice. Although the proportion and the activation status of CD4+ TCRα-β+ T cells in DKO mice were similar to those in TCRα-KO mice, signal transducer and activator of transcription 1, nuclear factor κB, and their target genes were hyperactivated in infiltrated mononuclear cells and colonic epithelial cells in DKO mice. Cytokine-depletion experiments showed that exacerbated colitis in the DKO mice was dependent on both IFNγ and IL-4. SOCS1-deficient cells were hypersensitive to IFNγ, IL-4, and lipopolysaccharides, depending on the target genes. Conclusions: SOCS1 plays an important role in preventing murine colitis by restricting the cytokine signals. SOCS1/TCRα DKO mice could be a useful model for investigating human IBD.

Original languageEnglish
Pages (from-to)373-388
Number of pages16
JournalGastroenterology
Volume130
Issue number2
DOIs
Publication statusPublished - 2006 Feb
Externally publishedYes

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Crohn Disease
Interleukin-4
Interferons
Knockout Mice
Cytokines
T-Cell Antigen Receptor
Colitis
STAT1 Transcription Factor
Antibodies
Inflammatory Bowel Diseases
Genes
Reverse Transcription
Lipopolysaccharides
Transcription Factors
Western Blotting
Epithelial Cells
Phosphorylation
T-Lymphocytes
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Gastroenterology

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Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNγ and IL-4 are involved. / Chinen, Takatoshi; Kobayashi, Takashi; Ogata, Hisanobu; Takaesu, Giichi; Takaki, Hiromi; Hashimoto, Masayuki; Yagita, Hideo; Nawata, Hajime; Yoshimura, Akihiko.

In: Gastroenterology, Vol. 130, No. 2, 02.2006, p. 373-388.

Research output: Contribution to journalArticle

Chinen, T, Kobayashi, T, Ogata, H, Takaesu, G, Takaki, H, Hashimoto, M, Yagita, H, Nawata, H & Yoshimura, A 2006, 'Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNγ and IL-4 are involved', Gastroenterology, vol. 130, no. 2, pp. 373-388. https://doi.org/10.1053/j.gastro.2005.10.051
Chinen, Takatoshi ; Kobayashi, Takashi ; Ogata, Hisanobu ; Takaesu, Giichi ; Takaki, Hiromi ; Hashimoto, Masayuki ; Yagita, Hideo ; Nawata, Hajime ; Yoshimura, Akihiko. / Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNγ and IL-4 are involved. In: Gastroenterology. 2006 ; Vol. 130, No. 2. pp. 373-388.
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AU - Takaki, Hiromi

AU - Hashimoto, Masayuki

AU - Yagita, Hideo

AU - Nawata, Hajime

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