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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
A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor β
Heike Dornhoff1, Christoph Becker, Stefan Wirtz
1Department of Medicine, University of Erlangen-Nuremberg, Erlangen and Nuremberg, Germany.
Background & Aims:
Transforming growth factor (TGF)-β signaling, which is down-regulated by the E3 ubiquitin ligase Smad ubiquitin regulating factor 2 (Smurf2), promotes development of cancer. We identified a splice variant of Smurf2 (ΔE2Smurf2) and investigated its role in colon carcinogenesis in mice.
Methods:
Colitis-associated colon cancer was induced in mice by administration of azoxymethane, followed by 3 cycles of oral administration of dextran sodium sulfate. Messenger RNA levels of Smurf2 in colon tumors and control tissue were measured by quantitative polymerase chain reaction; lymphocyte and cytokine levels were measured in tumor and tissue samples.
Results:
Tumor-infiltrating CD4(+) cells expressed higher levels of ΔE2Smurf2 than CD4(+) cells from nontumor tissues of wild-type mice. T cell-specific overexpression of ΔE2Smurf2 increased TGF-β signaling by suppressing protein levels of Smurf2, accompanied by an increase in levels of TGF-β receptor type II. Transgenic mice that overexpress ΔE2Smurf2 were protected against development of colitis-associated tumors and down-regulated proinflammatory cytokines such as interleukin-6. Patients with chronic inflammatory bowel disease had a significantly lower ratio of Smurf2/ΔE2Smurf2 than control individuals.
Conclusions:
T cell-specific ΔE2Smurf2 degrades wild-type Smurf2 and controls intestinal tumor growth in mice by up-regulating TGF-β receptor type II, reducing proliferation and production of proinflammatory cytokines.
Insights
A novel splice variant of Smad ubiquitin regulating factor 2 (Smurf2), named ΔE2Smurf2, was identified and found to protect against colon cancer in mice. T cell-specific ΔE2Smurf2 up-regulates TGF-β signaling, reducing tumor growth and inflammation.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Transforming growth factor (TGF)-β signaling is crucial for development but its dysregulation, particularly down-regulation by E3 ubiquitin ligase Smad ubiquitin regulating factor 2 (Smurf2), promotes cancer.
- A novel splice variant of Smurf2, designated ΔE2Smurf2, was identified, prompting investigation into its role in colon carcinogenesis.
Purpose of the Study:
- To investigate the role of the newly identified ΔE2Smurf2 splice variant in mouse models of colon cancer.
- To determine the molecular mechanisms by which ΔE2Smurf2 influences tumor growth and inflammation.
Main Methods:
- Colitis-associated colon cancer was induced in mice using azoxymethane and dextran sodium sulfate.
- Messenger RNA levels of Smurf2 and ΔE2Smurf2 were quantified using quantitative polymerase chain reaction.
- Lymphocyte and cytokine levels in tumor and tissue samples were measured.
Main Results:
- Tumor-infiltrating CD4(+) cells showed higher ΔE2Smurf2 expression compared to nontumor tissues.
- T cell-specific overexpression of ΔE2Smurf2 enhanced TGF-β signaling by reducing Smurf2 and increasing TGF-β receptor type II levels.
- Transgenic mice overexpressing ΔE2Smurf2 exhibited protection against colitis-associated tumors and reduced proinflammatory cytokines like interleukin-6.
Conclusions:
- T cell-specific ΔE2Smurf2 degrades wild-type Smurf2, thereby controlling intestinal tumor growth in mice.
- ΔE2Smurf2 exerts its tumor-suppressive effects by up-regulating TGF-β receptor type II, consequently reducing cell proliferation and the production of proinflammatory cytokines.
- A lower Smurf2/ΔE2Smurf2 ratio was observed in patients with chronic inflammatory bowel disease, suggesting a potential role in human disease.
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