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Science 1 September 2000:
Vol. 289. no. 5484, pp. 1560 - 1563
DOI: 10.1126/science.289.5484.1560
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Reports

Prokaryotic Regulation of Epithelial Responses by Inhibition of Ikappa B-alpha Ubiquitination

Andrew S. Neish,* Andrew T. Gewirtz, Hui Zeng, Andrew N. Young, Michael E. Hobert, Vinit Karmali, Anjali S. Rao, James L. Madara

Epithelia of the vertebrate intestinal tract characteristically maintain an inflammatory hyporesponsiveness toward the lumenal prokaryotic microflora. We report the identification of enteric organisms (nonvirulent Salmonella strains) whose direct interaction with model human epithelia attenuate synthesis of inflammatory effector molecules elicited by diverse proinflammatory stimuli. This immunosuppressive effect involves inhibition of the inhibitor kappa B/nuclear factor kappa B (Ikappa B/NF-kappa B) pathway by blockade of Ikappa B-alpha degradation, which prevents subsequent nuclear translocation of active NF-kappa B dimer. Although phosphorylation of Ikappa B-alpha occurs, subsequent polyubiquitination necessary for regulated Ikappa B-alpha degradation is completely abrogated. These data suggest that prokaryotic determinants could be responsible for the unique tolerance of the gastrointestinal mucosa to proinflammatory stimuli.

Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
*   To whom correspondence should be addressed. E-mail: aneish{at}emory.edu

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Overexpression of CRIP in transgenic mice alters cytokine patterns and the immune response.
L. Lanningham-Foster, C. L. Green, B. Langkamp-Henken, B. A. Davis, K. T. Nguyen, B. S. Bender, and R. J. Cousins (2002)
Am J Physiol Endocrinol Metab 282, E1197-E1203
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Lipoxin A4 Analogs Attenuate Induction of Intestinal Epithelial Proinflammatory Gene Expression and Reduce the Severity of Dextran Sodium Sulfate-Induced Colitis.
A. T. Gewirtz, L. S. Collier-Hyams, A. N. Young, T. Kucharzik, W. J. Guilford, J. F. Parkinson, I. R. Williams, A. S. Neish, and J. L. Madara (2002)
J. Immunol. 168, 5260-5267
   Abstract »    Full Text »    PDF »
Glucocorticoids Synergistically Enhance Nontypeable Haemophilus influenzae-induced Toll-like Receptor 2 Expression via a Negative Cross-talk with p38 MAP Kinase.
T. Shuto, A. Imasato, H. Jono, A. Sakai, H. Xu, T. Watanabe, D. D. Rixter, H. Kai, A. Andalibi, F. Linthicum, et al. (2002)
J. Biol. Chem. 277, 17263-17270
   Abstract »    Full Text »    PDF »
Small therapeutic molecules for the treatment of inflammatory bowel disease.
S J H van Deventer (2002)
Gut 50, iii47-53
   Abstract »    Full Text »    PDF »
The Salmonella typhimurium Flagellar Basal Body Protein FliE Is Required for Flagellin Production and to Induce a Proinflammatory Response in Epithelial Cells.
K. A. Reed, M. E. Hobert, C. E. Kolenda, K. A. Sands, M. Rathman, M. O'Connor, S. Lyons, A. T. Gewirtz, P. J. Sansonetti, and J. L. Madara (2002)
J. Biol. Chem. 277, 13346-13353
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Cutting Edge: Identification of c-Rel-Dependent and -Independent Pathways of IL-12 Production During Infectious and Inflammatory Stimuli.
N. Mason, J. Aliberti, J. C. Caamano, H.-C. Liou, and C. A. Hunter (2002)
J. Immunol. 168, 2590-2594
   Abstract »    Full Text »    PDF »
Morphologic and Molecular Characterization of Salmonella typhimurium Infection in Neonatal Calves.
R. L. Santos, S. Zhang, R. M. Tsolis, A. J. Baumler, and L. G. Adams (2002)
Vet. Pathol. 39, 200-215
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Enteric Bacteria Counteract Lipopolysaccharide Induction of Antimicrobial Peptide Genes.
H. Lindmark, K. C. Johansson, S. Stoven, D. Hultmark, Y. Engstrom, and K. Soderhall (2001)
J. Immunol. 167, 6920-6923
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Human Macrophage Gamma Interferon Decreases Gene Expression but Not Replication of Mycobacterium tuberculosis: Analysis of the Host-Pathogen Reciprocal Influence on Transcription in a Comparison of Strains H37Rv and CMT97.
G. Cappelli, P. Volpe, A. Sanduzzi, A. Sacchi, V. Colizzi, and F. Mariani (2001)
Infect. Immun. 69, 7262-7270
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Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells.
F. Sierro, B. Dubois, A. Coste, D. Kaiserlian, J.-P. Kraehenbuhl, and J.-C. Sirard (2001)
PNAS 98, 13722-13727
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