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Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis
Prema Robinson1, Kelsey Montoya1, Emily Magness1
1Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Background And Aims:
Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3.
Methods:
We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice.
Results:
Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases.
Conclusions:
Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
Insights
STAT3 inhibition with TTI-101 ameliorates dextran sodium sulfate (DSS)-induced colitis in mice. This suggests targeting STAT3 may treat inflammatory bowel disease (IBD) and prevent associated colorectal cancer (CRC).
Area of Science:
- Gastroenterology
- Immunology
- Oncology
Background:
- Inflammatory bowel disease (IBD) increases colorectal cancer (CRC) risk.
- Signal transducer and activator of transcription 3 (STAT3) has pro-inflammatory (STAT3α) and anti-inflammatory (STAT3β) isoforms.
- STAT3α promotes inflammation and inhibits apoptosis, while STAT3β has opposing effects.
Purpose of the Study:
- To investigate the role of STAT3 in dextran sodium sulfate (DSS)-induced colitis, a model for IBD.
- To determine the therapeutic potential of STAT3 inhibition in IBD and IBD-associated CRC.
Main Methods:
- DSS-induced colitis was established in wild-type (WT) mice and STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice.
- Mice were treated with TTI-101, a STAT3 inhibitor, or vehicle control.
- Clinical outcomes, immune cell infiltration, and gene expression were assessed.
Main Results:
- DSS-induced colitis was more severe in ΔβΔβ mice compared to WT mice.
- TTI-101 treatment significantly attenuated colitis severity in WT mice.
- TTI-101 increased CD4+ T-cell apoptosis, reduced IL-17+ cell infiltration, and downregulated STAT3 target genes.
Conclusions:
- STAT3 plays a critical role in the pathogenesis of IBD.
- Targeting STAT3 with small molecules like TTI-101 shows promise for treating IBD.
- STAT3 inhibition may be a strategy to prevent CRC in IBD patients.
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