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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0000000000000096
Original Basic Research Articles

Crohn's Disease–associated Escherichia coli Survive in Macrophages by Suppressing NFκB Signaling

Rahman, Khalidur PhD*,†; Sasaki, Maiko MS*,†; Nusrat, Asma MD; Klapproth, Jan-Michael A. MD*,†

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Abstract

Background:

Epidemiological and genetic studies suggest a role for enteric flora in the pathogenesis of Crohn's disease (CD). Crohn's disease–associated Escherichia coli (CDEC) is characterized by their ability to invade epithelial cells and survive and induce high concentration of TNF-α from infected macrophages. However, the molecular mechanisms of CDEC survival in infected macrophages are not completely understood.

Methods:

Intracellular survival of CDEC strain LF82 isolated from inflamed ileum tissue, 13I isolated from inflamed colonic tissue, and control E. coli strains were tested in the murine macrophage cell line, J774A.1 by Gentamicin protection assay. Modulation of intracellular cell signaling pathways by the E. coli strains were assessed by western blot analysis and confocal microscopy.

Results:

13I demonstrated increased survival in macrophages with 2.6-fold higher intracellular bacteria compared with LF82, yet both strains induced comparable levels of TNF-α. LF82 and 13I differentially modulated key mitogen-activated protein kinase pathways during the acute phase of infection; LF82 activated all 3 mitogen-activated protein kinase pathways, whereas 13I activated ERK1/2 pathway but not p38 and JNK pathways. Both 13I and LF82 suppressed nuclear translocation of NFκB compared with noninvasive E. coli strains during the acute phase of infection. However, unlike noninvasive E. coli strains, 13I and LF82 infection resulted in chronic activation of NFκB during the later phase of infection.

Conclusions:

Our results showed that CDEC survive in macrophages by initially suppressing NFκB activation. However, persistence of bacterial within macrophages induces chronic activation of NFκB, which correlates with increased TNF-α secretion from infected macrophages.

Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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