Prokaryotic Regulation of Epithelial Responses by Inhibition of IκB-α Ubiquitination

TLDR

Epithelia of the vertebrate intestinal tract maintain an inflammatory hyporesponsiveness toward lumenal prokaryotic microflora. The study aimed to identify nonvirulent Salmonella strains that directly attenuate inflammatory effector synthesis in human epithelial models. The suppression occurs by blocking IκB‑α degradation, preventing NF‑κB nuclear translocation, and abolishing the polyubiquitination step required for IκB‑α turnover. These strains reduce inflammatory effector production, indicating that prokaryotic determinants may underlie gastrointestinal mucosal tolerance to proinflammatory stimuli.

Abstract

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 κB/nuclear factor κB (IκB/NF-κB) pathway by blockade of IκB-α degradation, which prevents subsequent nuclear translocation of active NF-κB dimer. Although phosphorylation of IκB-α occurs, subsequent polyubiquitination necessary for regulated IκB-α degradation is completely abrogated. These data suggest that prokaryotic determinants could be responsible for the unique tolerance of the gastrointestinal mucosa to proinflammatory stimuli.