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

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 alpha (TCR alpha) double knockout (DKO) mice. Methods: The depletion of interferon gamma (IFN gamma) and IL-4 was achieved by crossing the DKO mice with IFN gamma 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 1.00% of the DKO mice within 9 weeks of age than in TCR alpha-KO mice. Although the proportion and the activation status of CD4(+) TCR alpha(-)beta(+) T cells in DKO mice were similar to those in TCR alpha-KO mice, signal transducer and activator of transcription 1, nuclear factor KB, 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 IFN gamma and IL-4. SOCS:I-deficient cells were hypersensitive to IFN gamma, 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/TCR alpha DKO mice could be a useful model for investigating human IBD.