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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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