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Infection and Immunity, October 2008, p. 4677-4685, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00227-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tumor Suppressor Foxo3a Is Involved in the Regulation of Lipopolysaccharide-Induced Interleukin-8 in Intestinal HT-29 Cells{triangledown}

Lobke Snoeks,1 Christopher R. Weber,2 Jerrold R. Turner,2 Mitra Bhattacharyya,1 Kaarin Wasland,1 and Suzana D. Savkovic1*

Department of Medicine, Division of Gastroenterology, Evanston-Northwestern Research Institute, Evanston, Illinois 60201,1 Department of Pathology, The University of Chicago, Chicago, Illinois 606372

Received 18 February 2008/ Returned for modification 25 March 2008/ Accepted 21 July 2008

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 I{kappa}B{alpha}, an NF-{kappa}B 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 I{kappa}B{alpha}.

* Corresponding author. Mailing address: Evanston-Northwestern Research Institute, Department of Medicine, Division of Gastroenterology, 1001 University Place, Room 314, Evanston, IL 60201. Phone: (224) 364-7404. Fax: (847) 733-5041. E-mail: SSavkovic{at}enh.org

{triangledown} Published ahead of print on 4 August 2008.

Editor: B. A. McCormick

Infection and Immunity, October 2008, p. 4677-4685, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00227-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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