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

Wen Zhou, Qian Cao, Yan Peng, Qing Jun Zhang, Diego H. Castrillon, Ronald A. DePinho, Zhi Ping Liu

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

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-γ and tumor necrosis factor-α 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-κB (NF-κB), and Foxo4 deficiency is associated with increased NF-κB 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-κB and identify a novel function of FoxO4 in the regulation of NF-κB-mediated mucosal immunity.

Original languageEnglish (US)
Pages (from-to)1403-1414
Number of pages12
JournalGastroenterology
Volume137
Issue number4
DOIs
StatePublished - Oct 2009

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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