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Updated: Aug 15, 2026
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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
OTUD5 Maintains STAT1/2 Stability and Promotes IFNγ-driven Intestinal Inflammation
Huiyuan Guan1, Changzhou Cai2, Jiewei Wang2
1Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang 310058, China.
The Journal of Biological Chemistry
|August 13, 2026
Summary
Scientists discovered that OTUD5 protein drives inflammation in Inflammatory Bowel Disease (IBD) and resistance to anti-TNFα therapies. Inhibiting OTUD5 with CT1170 reduced inflammation and halted disease progression in models.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Inflammatory Bowel Disease (IBD) involves persistent mucosal inflammation, often driven by TNFα and IFNγ.
- Anti-TNFα biologics are standard treatments, but therapeutic resistance is a major clinical challenge.
- Mechanisms sustaining inflammation in non-responders are not fully understood.
Purpose of the Study:
- To investigate the role of deubiquitinase OTUD5 in anti-TNFα therapy resistance in IBD.
- To elucidate the molecular mechanisms by which OTUD5 contributes to IFNγ-driven inflammation.
- To evaluate the therapeutic potential of targeting OTUD5 with a small-molecule inhibitor.
Main Methods:
- Analysis of human colon biopsies from IBD patients (responders vs. non-responders).
- Generation and use of an intestinal epithelial cell-specific Otud5 knockout mouse model.
- Dextran sulfate sodium (DSS)-induced colitis model to assess inflammation and monocyte infiltration.
- Investigation of IFNγ-induced OTUD5 expression and its effect on STAT1/STAT2 stability.
- Assessment of the small-molecule inhibitor CT1170 in mouse models and human IBD organoids.
Main Results:
- OTUD5 was significantly upregulated in IBD non-responders.
- Otud5 deficiency in mice reduced IFNγ-dependent colitis severity and Ly6C+ monocyte infiltration.
- IFNγ non-transcriptionally induces OTUD5, which stabilizes STAT1/STAT2, sustaining IFNγ-ISGF3 signaling.
- OTUD5 promotes CCL8 expression, crucial for monocyte recruitment.
- CT1170 inhibited the IFNγ-ISGF3-CCL8 axis, halted colitis, and suppressed colitis-associated tumorigenesis.
- CT1170 disrupted IFNγ-driven inflammatory signaling in human IBD organoids.
Conclusions:
- OTUD5 is a key mediator of IFNγ-driven inflammation and anti-TNFα therapy resistance in IBD.
- The OTUD5-STAT1/STAT2-CCL8 axis represents a novel therapeutic target for IBD.
- The small-molecule inhibitor CT1170 shows promise for treating IBD by targeting this pathway.
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