Tumor suppressor Foxo3a is involved in the regulation of lipopolysaccharide-induced interleukin-8 in intestinal HT-29 cells.
Enteric bacteria and their products play an important role in intestinal inflammation; however, the complete mechanisms are not elucidated yet. Tumor suppressor Foxo3a regulates gene expression in the nucleus, and its translocation to the cytosol leads to inactivation. Proximally, Foxo3a is regulated by different pathways including the phosphoinositide 3-kinase (PI3K) pathway. The aim of this study was to determine the effect of bacterial infection on Foxo3a in intestinal epithelial cells and to examine the contribution of Foxo3a in intestinal inflammation. Bacterial lipopolysaccharide (LPS) and infection with mouse pathogen Citrobacter rodentium induce translocation of the nuclear Foxo3a into the cytosol, where it degrades in human HT-29 and mouse CMT-93 cells. In colonic epithelia of healthy mice, Foxo3a is localized in the epithelia at the bottom of the crypts in both the nucleus and the cytosol, while in C. rodentium-infected colon Foxo3a is expressed along the crypts and located mainly in the cytosol, suggesting its inactivation. LPS utilized the PI3K pathway to inhibit Foxo3a. Additionally, inhibition of PI3K attenuated LPS-induced proinflammatory interleukin-8 (IL-8). LPS-induced IL-8 is increased in HT-29 cells with silenced Foxo3a. Moreover, in HT-29 cells with silenced Foxo3a, the amount of IkappaBalpha, an NF-kappaB inhibitor, is decreased. In conclusion, LPS and bacterial infection inactivate Foxo3a in intestinal epithelia via the PI3K pathway and inactivated Foxo3a leads to the upregulation of IL-8 by suppressing inhibitory IkappaBalpha.
Snoeks
Lobke
L
Department of Medicine, Division of Gastroenterology, Evanston-Northwestern Research Institute, Evanston, Illinois 60201, USA.
Weber
Christopher R
CR
Turner
Jerrold R
JR
Bhattacharyya
Mitra
M
Wasland
Kaarin
K
Savkovic
Suzana D
SD
D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology*; D003106:Colon / Q000276:immunology / Q000382:microbiology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism
C508606:CXCL8 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016209:Interleukin-8; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases