Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination

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 (I kappa B/NF-kappa B) pathway by blockade of I kappa B-alpha degradation, which prevents subsequent nuclear translocation of active NF-kappa B dimer, Although phosphorylation of I kappa B-alpha occurs, subsequent polyubiquitination necessary for regulated I kappa 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.