Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNgamma and IL-4 are involved.
OBJECTIVE
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 alpha (TCRalpha) double knockout (DKO) mice.


METHODS
The depletion of interferon gamma (IFNgamma) and IL-4 was achieved by crossing the DKO mice with IFNgamma 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 TCRalpha-KO mice. Although the proportion and the activation status of CD4(+) TCRalpha(-)beta(+) T cells in DKO mice were similar to those in TCRalpha-KO mice, signal transducer and activator of transcription 1, nuclear factor kappaB, 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 IFNgamma and IL-4. SOCS1-deficient cells were hypersensitive to IFNgamma, 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/TCRalpha DKO mice could be a useful model for investigating human IBD.
Chinen
Takatoshi
T
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Kobayashi
Takashi
T
Ogata
Hisanobu
H
Takaesu
Giichi
G
Takaki
Hiromi
H
Hashimoto
Masayuki
M
Yagita
Hideo
H
Nawata
Hajime
H
Yoshimura
Akihiko
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000503:physiopathology*; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
D002352:Carrier Proteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015847:Interleukin-4; D007371:Interferon-gamma