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Blockade of STAT3 by antisense oligonucleotide in TNBS-induced murine colitis
AiPing Bai1, PinJin Hu, Jie Chen
1Department of Gastroenterology, The first affiliated hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
Background And Aims:
The expression of signal transducers and activators of transcription 3 (STAT3) is increased in Crohn's disease (CD), and nuclear translocated STAT3 is also found in the disease. However, the role of STAT3 protein on the pathogenesis of CD is not clear. This study was executed to investigate the role of STAT3 protein on the pathogenesis of trinitrobenzene sulfonic acid (TNBS)-induced colitis, the pathogenesis of which is CD-like.
Methods:
TNBS-induced colitis was produced, and STAT3 antisense oligonucleotide was administrated intracolonically during the early phase of colitis. The mice were killed 7 days later, and the expressions of STAT3 and phosphorylated STAT3 were identified by Western blot and immunofluorescence. The lamina propria mononuclear cells (LPMCs) were isolated freshly, and the percent of cell death and the expressions of Bcl-2 and Bax in LPMCs were evaluated. Colonic tissue damage and the production of inflammatory cytokines were measured also.
Results:
Administration of STAT3 antisense oligonucleotide effectively inhibited STAT3 expression and phosphorylation in inflamed colonic mucosa of colitis. The mice that were administered STAT3 antisense oligonucleotide showed less colonic tissue damage with decreased production of inflammatory cytokines such as TNF-alpha and INF-gamma in mucosa compared with that of those TNBS-induced colitis. Administration of STAT3 antisense oligonucleotide successfully induced apoptosis of LPMCs and counteracted the unbalanced expressions of Bcl-2 and Bax in LPMCs from colitis.
Conclusions:
STAT3 activation may play an important role in the inflammatory process of TNBS-induced colitis, and inhibiting STAT3 activation during the early phase of the inflammatory response may have a beneficial effect on the colitis.
Insights
Inhibiting signal transducers and activators of transcription 3 (STAT3) in early-stage colitis reduced inflammation and tissue damage. This suggests STAT3 plays a key role in Crohn's disease-like inflammation.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Signal transducers and activators of transcription 3 (STAT3) expression is elevated in Crohn's disease (CD).
- The precise role of STAT3 in CD pathogenesis remains unclear.
- This study investigates STAT3's role in trinitrobenzene sulfonic acid (TNBS)-induced colitis, a model for CD.
Purpose of the Study:
- To elucidate the role of STAT3 protein in the pathogenesis of TNBS-induced colitis.
- To evaluate the therapeutic potential of inhibiting STAT3 in colitis.
Main Methods:
- TNBS-induced colitis model in mice.
- Intracolonic administration of STAT3 antisense oligonucleotide during early colitis.
- Assessment of STAT3 expression, phosphorylation, colonic tissue damage, inflammatory cytokine production (TNF-alpha, INF-gamma), and apoptosis in lamina propria mononuclear cells (LPMCs).
Main Results:
- STAT3 antisense oligonucleotide effectively suppressed STAT3 expression and phosphorylation in inflamed colonic mucosa.
- Mice treated with STAT3 antisense oligonucleotide exhibited reduced colonic tissue damage and lower levels of TNF-alpha and INF-gamma.
- STAT3 inhibition promoted apoptosis in LPMCs and normalized Bcl-2 and Bax expression.
Conclusions:
- STAT3 activation is implicated in the inflammatory processes of TNBS-induced colitis.
- Early-phase inhibition of STAT3 activation demonstrates therapeutic benefits for colitis.
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