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Updated: Jun 22, 2026
Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation
1Departmentsof Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Background & Aims:
FoxO4 is a member of the forkhead box transcription factor O (FoxO) subfamily. FoxO proteins are involved in diverse biological processes. In this study, we examine the role of FoxO4 in intestinal mucosal immunity and inflammatory bowel disease (IBD).
Methods:
Foxo4-null mice were subjected to trinitrobenzene sulfonic acid (TNBS) treatment. Microarray analysis and quantitative reverse transcription polymerase chain reaction were used to identify the cytokine transcripts that were altered by Foxo4 deletion. The effects of Foxo4 deficiency on the intestinal epithelial permeability and levels of tight junction proteins were examined by permeable fluorescent dye and Western blot. The molecular and cellular mechanisms by which FoxO4 regulates the mucosal immunity were explored through immunologic and biochemical analyses. The expression level of FoxO4 in intestinal epithelial cells of patients with IBD was examined with immunohistochemistry.
Results:
Foxo4-null mice were more susceptible to TNBS injury-induced colitis. The chemokine CCL5 is significantly up-regulated in the colonic epithelial cells of Foxo4-null mice, with increased recruitment of CD4(+) intraepithelial T cells and up-regulation of cytokines interferon-gamma and tumor necrosis factor-alpha in the colon. Foxo4 deficiency also resulted in an increase in intestinal epithelial permeability and down-regulation of the tight junction proteins ZO-1 and claudin-1. Mechanistically, FoxO4 inhibited the transcriptional activity of nuclear factor-kappaB (NF-kappaB), and Foxo4 deficiency is associated with increased NF-kappaB activity in vivo. FoxO4 transcription is transiently repressed in response to TNBS treatment and in patients with IBD.
Conclusion:
These results indicate that FoxO4 is an endogenous inhibitor of NF-kappaB and identify a novel function of FoxO4 in the regulation of NF-kappaB-mediated mucosal immunity.
Insights
FoxO4 acts as an inhibitor of NF-kappaB, playing a crucial role in regulating intestinal mucosal immunity. Its deficiency exacerbates inflammatory bowel disease (IBD) by increasing NF-kappaB activity and susceptibility to colitis.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- FoxO4 belongs to the forkhead box transcription factor O (FoxO) subfamily, involved in various biological processes.
- The role of FoxO4 in intestinal mucosal immunity and inflammatory bowel disease (IBD) requires further investigation.
Purpose of the Study:
- To elucidate the function of FoxO4 in intestinal mucosal immunity.
- To determine the involvement of FoxO4 in the pathogenesis of inflammatory bowel disease (IBD).
Main Methods:
- Utilized Foxo4-null mice subjected to trinitrobenzene sulfonic acid (TNBS)-induced colitis.
- Employed microarray analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to assess cytokine transcript alterations.
- Investigated intestinal epithelial permeability, tight junction protein levels, and molecular mechanisms through biochemical and immunologic analyses.
- Examined FoxO4 expression in intestinal epithelial cells of IBD patients via immunohistochemistry.
Main Results:
- Foxo4-null mice exhibited increased susceptibility to TNBS-induced colitis, characterized by elevated CCL5 chemokine levels and recruitment of CD4(+) T cells.
- Foxo4 deficiency led to increased intestinal epithelial permeability and decreased expression of tight junction proteins ZO-1 and claudin-1.
- FoxO4 was identified as an endogenous inhibitor of nuclear factor-kappaB (NF-kappaB), with its deficiency associated with heightened NF-kappaB activity.
- FoxO4 expression was transiently repressed in response to TNBS treatment and in IBD patients.
Conclusions:
- FoxO4 functions as an endogenous inhibitor of NF-kappaB.
- FoxO4 plays a novel regulatory role in NF-kappaB-mediated intestinal mucosal immunity.
- FoxO4 deficiency contributes to the pathogenesis of IBD by impairing mucosal barrier function and promoting inflammation.
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