FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation.
OBJECTIVE
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.


CONCLUSIONS
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.
Zhou
Wen
W
Departmentsof Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Cao
Qian
Q
Peng
Yan
Y
Zhang
Qing-Jun
QJ
Castrillon
Diego H
DH
DePinho
Ronald A
RA
Liu
Zhi-Ping
ZP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010539:Permeability; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D019108:Tight Junctions / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D016207:Cytokines; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D014302:Trinitrobenzenesulfonic Acid