FoxO4 Inhibits NF-κB and Protects Mice Against Colonic Injury and Inflammation

Departmentsof Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Gastroenterology (Impact Factor: 16.72). 07/2009; 137(4):1403-14. DOI: 10.1053/j.gastro.2009.06.049
Source: PubMed


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).
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.
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.
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.

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Available from: Yan Peng, Jan 13, 2015
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    • "Global deletion of FOXO3 is not lethal but affects lymph proliferation, widespread organ inflammation [4], age-dependent infertility [3], and decline in the neural stem cell pool [5]. Global deletion of FOXO4 exacerbates colitis in response to inflammatory stimuli [6]. Global deletion of FOXO6 displays normal learning but impaired memory consolidation [7]. "
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    • "FOXO transcription factors are activated under proinflammatory and oxidative environments via post-translational modifications by a variety of kinases including JNK [36] [37] causing nuclear translocation. Although FOXO1 and 3a have been shown to promote pro-inflammatory environments [38] [39], FOXO4 activation has been shown to be protective against inflammation and oxidative stress [40] [41]. In unrelated studies, we observed FOXO4 to be the highest expressed FOXO isoform in the placenta (unpublished data); therefore FOXO4 may serve as an adaptive mechanism for the placenta to respond to cellular stress. "
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    • ". FOXO1 deficiency induces inflammatory bowel disease [108], which is also shown in FOXO4-deficient mice [109]. However, in neutrophilic inflammation, such as rheumatoid arthritis and peritonitis, FOXO3 levels are elevated and required to suppress proapoptotic responses in neutrophils [110] [111]. "
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